Our drives are largely governed by two small primitive brain structures, the hypothalamus and the amygdala – shown in red in the drawing at right.  Remarkably, these two tiny structures are respectively the size of a pea and an almond — representing less than 1% of the brain’s three pounds of neural matter. Together, they constitute the control center of the paleomammalian brain–the “limbic” brain that governs our basic urges and desires as well as our homeostatic “set points” for temperature, sleep, body fat and behavioral urges like sex drive and aggression.

You can attempt to change your behavior by conscious determination and cognitive therapies.  But most attempts at intentional change are temporary and are doomed to fail in the long term because they are strongly resisted by powerful homeostatic processes encoded in our limbic brain.  Modern medicine recognizes the importance of homeostatic drives, and has developed pharmaceuticals to override them with diet pills, sleeping pills and antidepressants.  In fact, these medications do shift the balance of neurotransmitters and neural activity — at least in the short term.  But such chemical interventions are short-sighted “crutches” that promote dependency and come with side effects.  Often they exhibit  a “tolerance” effect: the brain’s control system fights back and weakens the impact of the medication.  To maintain the benefit, doses are increased, but this strategy may not always work.

This article will explain how the hypothalamus and amygdala contribute to the regulation of basic drives like eating, sleeping and sexuality, and how the amygdala can actually override the hypothalamus by enhancing the reward value of foods and other stimuli. (As I will explain, however, my take on “food reward” is different from that of Stephan Guyenet and other advocates of the Food Reward Hypothesis). This dual-control model can help explain anomalies such as obesity, addiction, and disordered sleep.

Finally,  I will provide suggestions on effective and natural ways to re-program the hypothalamus and amygdala and change your homeostatic set points, using the principle of hormesis.

Hormesis. Readers of this blog are familiar with hormesis:  a biological process whereby a beneficial effect (improved health, stress tolerance, growth or longevity) results from exposure to judicious doses of an agent that is otherwise detrimental at higher doses.  The many examples of homesis we’ve discussed on this blog involve adaptations that roughly fall into three categories.  The first two categories are quite well-known:

Structural adaptations to organs and tissues:

• Muscular growth, from weight lifting
• Adaptations of the foot and leg, from barefoot running
• Reversal of myopia, from use of anti-corrective lenses
• Other examples: calluses, suntanning

Defensive adaptations against foreign subtances:

• Immunotherapy to overcome allergies
• Endogenous defenses against oxidants and “xenobiotic” toxins

The third category is perhaps a less well recognized form of hormesis:

 ”Psycho-metabolic” adaptations:

• Hormonal and enzymatic adaptations to caloric restriction and fasting
• Psychological and weight loss benefits of cold showers
• Cue exposure therapy to overcome addictions
• Sleep restriction therapy to counteract insomnia

Psycho-metabolic adaptations. Let’s now expand upon this third category of adaptations, focusing on how certain types of stimulus or “stress” can bring about long term changes within the brain’s control system — the hypothalamus and amygdala.  These adaptations can induce broad sets of changes to your metabolism and psychological functioning.   These changes are long term adaptations — to be distinguished from short term or “artificial” changes that can temporarily induce weight loss, boost metabolism, energy level, wakefulness, or sex drive.   A true change in “set point” requires a sustainable physiological change that is reflected in real alterations in neuron density or receptor sensitivity within the brain.  In turn, these changes to the brain result in systemic changes elsewhere in the body.

In previous posts, I’ve touched upon a few topics that relate to the general thesis of psycho-metabolic adaptations that involve changes to the brain:

1. In “Change your receptors, change your set point“, I presented evidence that individuals suffering from obesity, addiction and depression have in common a down-regulation (reduction in the number or sensitivity) of dopamine receptors. In depression, receptors for other neurotransmitters such as serotonin are also down-regulated, a problem that can actually be made worse by chronic use of SSRI antidepressants.  The article also summarized research indicating that intense exercise, caloric restriction and intermittent fasting can up-regulate dopamine receptors and thereby provide a sustainable treatment for certain types of obesity, addiction and depression.
2. In  ”Obesity starts in the brain“, I outlined the Hypothalamic Hypothesis, a brain-centric analysis of obesity.  I argued that there are two different types of obesity–intra-abdominal and subcutaneous obesity–and that these conditions respectively result from  impairments to the insulin sensitivity or leptin sensitivity of a specific part of the hypothalamus — the arcuate nucleus.  Furthermore, it is the hypothalamic impairments that are primary; for example, insulin resistance starts in the brain and later spreads to the liver and muscles.  The article pointed to specific dietary and inflammatory factors that can improve hypothalamic sensitivity to these hormones and reverse obesity.

I will now build upon the Hypothalamic Hypothesis to account for the influence of the amygdala, to consider how the limbic system governs for drives other than eating, and to propose more generally how we can influence the brain’s control system.

The limbic system. Think about this:  By weight, about 85% of the human brain is the elaborate cerebral cortex, devoted to complex perceptual and conceptual processing and executive function.  In contrast, only a tiny piece of the brain is responsible for the full gamut of motivational drives and emotions, and for maintaining the balance of homeostatic functions like metabolism, body temperature, sleep and energy level.  The simultaneous management of all of these diverse functions is tightly packed into two nut-sized structures–evidently without getting signals crossed! When you think about it, this fact is quite astonishing.  It baffles me that, despite great popular interest in neuroscience, there has been so little commentary about this striking fact.

You can think of the the massive cortex as merely an elaborate pattern recognition system wrapped around the limbic brain.  The cortex’s pattern recognition system has evolved to improve the quality of information being fed to the tiny thermostatic hypothalamus and amygdala.  While the cortex gives us a huge advantage over other animals in analyzing our environment, we seem not to much real control over basic drives like eating and sleeping.  Despite the evolutionary achievement of “rationality”, we humans remain to a large extent at the mercy of our basic animal drives and emotions.

Things are not so bleak, however, once we recognize what makes the limbic brain tick.  While we may not have direct volitional control over the limbic system, there are actions we can take to influence the balance of neural forces within the hypothalamus and amygdala. Over time, we can literally reprogram our psycho-metabolic control systems.

But first a little anatomy.   And I’ll try to keep things simple.  The point of this interlude is not to teach anatomy, but rather to highlight a few key parts of the limbic control system and how they function. I’ve borrowed much of the following discussion from the excellent and incisive monograph, The Limbic System, by Rhawn Joseph, much of which is also contained in Chapter 4 of his online Brain e-book.

The figure below provides a “macro” view of the major parts of the limbic system.  Located at the center of the brain, perched atop the brainstem, the limbic system includes not only the hypothalamus and amygdala, but other structures such as the hippocampus, cingulate gyrus, pituitary gland.  But particularly note that the amygdala is connected tightly by numerous nerve bundles to the hypothalamus.  The amygdala acts directly on the hypothalamus to control hypothalamic drives, and conversely, the hypothalamus “uses” the amygdala (and to some extent the septum) as a window on the world to satisfy its drives by selectively searching out appropriate foods, potential mates, and sleep and exercise opportunities.

Furthermore, notice that the amygdala is closely connected to the olfactory bulb, and mediates its connections to the hypothalamus.  As Joseph notes, “The hypothalamus is exceedingly responsive to olfactory (and pheromonal) input. Perhaps reflecting this partial and putative olfactory origin is the fact that this structure utilizes chemical (hormonal, humoral) molecules to communicate with other areas of the brain, and reacts to these same molecules as well as olfactory cues, including those directly related to sexual status.”  We will come back to the under appreciated importance of olfactory cues in the limbic system’s control of basic drives, particularly appetite and sexual/social attraction.

For present purposes, there are four important points to understand about the actions of the hypothalamus and the amygdala:

1. The hypothalamus is purely reactive. The hypothalamus regulates drives, but is almost totally “blind” to the outside world.  It is inwardly focused and responds reflexively.  It has no memory and acts “in the moment”.   According to Joseph, the hypothalamus is the physical embodiment of the Freudian id:

Emotional functioning at the level of the hypothalamus is not only quite limited and primitive, it is also largely reflexive… Emotions elicited by the hypothalamus are largely undirected, short-lived, being triggered reflexively and without concern or understanding regarding consequences; that is, unless chronically stressed or aroused. Nevertheless, direct contact with the real world is quite limited and almost entirely indirect as the hypothalamus is largely concerned with the internal environment of the organism. Although it receives and responds to light, it cannot “see”. It has no sense of morals, danger, values, logic, etc., and cannot feel or express love or hate. Although quite powerful, hypothalamic emotions are largely undifferentiated, consisting of feelings of pleasure, unpleasure, rage, hunger, thirst, etc….it tends to serve what Freud (1911) has described as the pleasure principle. Functionally isolated, the hypothalamus at birth has no way of reducing tension of mobilizing the organism for any form of effective action. It is helpless. When tensions associated with immediate needs (e.g. hunger or thirst) become unpleasant the only response available to the hypothalamus is to cry and make rage-like vocalization. When satiated, the hypothalamus can only respond with a feeling state suggesting pleasure or at least quiescence.

2. The hypothalamus operates through a hierarchy of channels.  The hypothalamus receives information about the state of the organism, and in turn sends “commands”,  through three main channels:

• The bloodstream. Many signals are exchanged through the relatively porous blood-brain barrier.  For example, as discussed in my previous post on obesity, the hypothalamus receives and integrates a range of signals about short term nutrient status (glucose and fatty acids), gut signals (ghrelin, PYY and CCK) and longer term energy storage  (hormones like insulin, glucagon, leptin and adiponectin).   The blood also carries similar signals regarding body temperature, wakefulness and sleep, and state of readiness for action. And the hypothalamus activates the section of neuroendocrine activators via other glands like the pituitary, thyroid and adrenal glands.
• Nerve fibers –”afferents” and “efferents”.  Certain communication is done via nerve fibers. For example, appetite cues are provided from the nose via the olfactory bulb and from the gut via the vagus nerve.  Body temperature cues are provided from remote thermoreceptors.  The sleep-wake cycle is calibrated by neural inputs from the suprachiasmatic nucleus (SCN), which responds to dark and light cycles.  And conversely, the hypothalamus uses efferent nerves to remotely regulate adrenal glands and digestive organs.
• Higher order inputs.  The above chemical and neural inputs can be modulated or overridden by “emotional” interpretation of perceptual and cognitive inputs.  This is is where the amygdala comes in.

3. The amygdala is the “handmaiden” of the hypothalamus.  It serves as the emotional eyes and ears for the hypothalamus by translating the input of the senses and the great pattern recognition capability of the higher cortex into emotional responses that feed into the hypothalamus.  Going beyond the undifferentiated, spur-of-the moment emotional drives of the hypothalamus, the amygdala provides a highly selective response to specific and often complex sensory stimuli.  As Joseph explains:

In contrast to the primitive hypothalamus, the more recently developed amygdala (the “almond”) is preeminent in the control and mediation of all higher order emotional and motivational activities. Via it’s rich interconnections with various neocortical and subcortical regions, amygdaloid neurons are able to monitor and abstract from the sensory array stimuli that are of motivational significance to the organism. This includes the ability to discern and express even subtle social-emotional nuances such as friendliness, fear, love, affection, distruct, anger, etc., and at a more basic level, determine if something might be good to eat.  In fact, amygdaloid neurons respond selectively to the flavor of certain preferred foods, as well as to the sight or sound of something that might be especially desirable to eat  including even the sight of drugs that induce extreme pleasure…Belying its involvement in emotion, including the pleasure associated with cocaine usage, is the unique chemical anatomy of the amygdala, which is rich in a variety of neuropetides including enkephalins and beta-endorphins as well as opiate receptors. In fact, of all brain regions, the greates concentration of opiate receptors is found within the human amygdala.

Beyond appetite, the amygdala also provides a selective filter on sensory cues related to other drives such as sociality and sexual attractiveness.  Of significant note, the amygdala is the arbiter of very specific social cues such as facial recognition:

The amygdala is exceedingly responsive to social and emotional stimuli as conveyed vocally, through touch, sight, and via the expressions of the face . In fact, the amygdala, as well as the overlying (and partly coextensive) temporal lobe, contains neurons which respond selectively to smiles and to the eyes, and which can differentiate between male and female faces and the emotions they convey. For example, the left amygdala acts to discriminate the direction of another person’s gaze, whereas the right amygdala becomes activated while making eye-to-eye contact …Moreover, the normal human amygdala typically responds to frightened faces by altering its activity, whereas injury to the amygdala disrupts the ability to recognize faces. With bilateral destruction, emotional speech production and the capacity to respond appropriately to social emotionally stimuli is abolished.

Maybe this explains why Seth Roberts observation that looking at faces in the morning makes people happy–a simple anti depression therapy!

Joseph also notes that “The relationship between hypothalamus and amygdala is bidirectional.  The amygdala interprets sensory information and emotions and passes these inputs on to the hypothalamus to initiate drives. And when a drive like hunger or sex emerges, the amygdala helps out by surveying the environment for suitable choices of food or potential sexual partners.”

4. The hypothalamus and amygdala  are composed of opposing sets of neural clusters or “nuclei”.   These pairs of neural clusters act in an oscillating ying-and-yang fashion to achieve homeostasis. In both the hypothalamus and amygdala, the external or lateral nuclei activate the parasympathetic nervous system, associated with hunger and digestion, pleasure, relaxation and sexual arousal.  In the case of appetite, stimulation of neurons in the lateral hypothalamus (LH) increases  appetite, releases serotonin and dopamine, and activates anabolic storage of  glucose and fatty acids,  In opposition to the lateral nuclei, internal or “medial” nuclei activate the sympathetic (“fight or flight”) nervous system, which readies the organism for action, increases heart rate, suppresses appetite and sexual desire, stimulates release of acetylcholine and norepinephrine, and activates catabolic mobilization of nutrients such as fat or glycogen.  Stimulation of the medial nuclei are also associated with “aversive” non-pleasurable sensation.

Similar pairings of opposing limbic nuclei exist for neurons that control thirst, body temperature, the sleep/wake cycle, or activate social or sexual arousal.

The amygdala has a parallel structure to that of the hypothalamus, which allows direct two-way communication between them.   As Joseph notes:

Moreover, through the massive interconnections maintained with the lateral and medial (ventromedial) hypothalamus, the amygdala is able to act directly on this structure, driving the hypothalamus, so to speak, and thus tapping into its emotional reserviour so that its ends may be met. Indeed, it is able to modulate hypothalamic activity through inhibitory and excitatory projections to this structure. Direct stimulation of the basolateral amygdala and the ventral amydalofugal pathway excites the principle neurons of the medial hypothalamus. By contrast, stimulation of the medial (ventro-medial) amygdala and the stria terminalis pathway, inhibits these same hypothalamic neurons. Hence, whereas the lateral amydala exerts excitatory influences on the hypothalamus, the medial amygdala exerts inhibitory influences, and can thus control, or at least exert excitatory/inhibitory and thus modulatory influences on hunger, thirst, sexual arousal, rage, etc., as well as hormonal, endocrine, and other functions associated with the hypothalamic nuclues. Indeed, the amygdala can be likened to the chief executive of the limbic system and weilds enormous power via its control over the hypothalamus.

Similar sets of paired hypothalamic and amydaloid nuclei govern the balances that control thirst, body temperature, sleep and sex drive.  For example, osmoreceptors that monitor the concentration of salt ions in blood control thirst, and respond by adjusting the hormone vasopressin to regulate water retention by the kidney. Thermoceptors in the body and hypothalamus activate different nuclei in the hypothalamus.

Generalized versus conditioned desires. By serving as the “interpreter” that provides higher-level emotive “meaning” to raw sensory inputs, the amygdala plays a prominent role in learning and laying down reward circuitry.  In effect, it turns complex sensory inputs into cues that the hypothalamus can act upon by establishing Pavlovian circuits that automate the way your basic drives respond to the external environment and even your thoughts.  This applies to both attractive (stimulatory) and aversive (inhibitory) stimuli. As mentioned above, the reward circuitry utilizes a high concentration of dopaminergic neurons to reinforce powerful learned responses of the hypothalamus to sensory cues and thought patterns.

While the hypothalamus activates generalized drives and provides hard-wired low-level responses to universal and fairly general cues, the amygdala provides finely tuned and highly specific learned responses that can modify or override these low level cues:

The hypothalamus gets hungry and anything will do…,but the amygdala is picky about which foods it likes or dislikes, to the point of craving a specific type of chocolate with a certain texture, or rejecting a wine with a slight off-note
The hypothalamus wants sex…but the amygdala is selective about what turns it on — down to very fine preferences regarding appearance, aroma, or even sense of humor.  It may be so selective as to be monogamous!
The hypothalamus wants to sleep… but the amygdala picks up cues about danger that can rally your alertness.

The key point is this:   The generic drives of the hypothalamus are equally powerful whether they are activated by low level chemical and nerve inputs from the blood stream or stomach nerves — or rather by higher level perceptual and emotional inputs from the amygdala.  And if the reward circuitry from the amygdala is strong enough, it can override the low level signals.   A Pavlovian response to the aroma of a juicy steak or the sight of a decadent chocolate cake can activate the hunger response and fat storage program initiated in the lateral hypothalamus, regardless of the nutritional state conveyed by blood glucose or leptin and insulin levels.  Conversely, an unappetizing meal, or an emotional shock can quickly suppress appetite or activate a state of arousal and access to energy.

The hypothalamus doesn’t know or care why it is getting hungry, sleepy or sexed up.   It matters not whether the signals are based on blood chemicals or high level emotional perception — the actions taken by the hypothalamus are identical in either case.

An aside on food reward. This dual model of direct hypothalamic regulation versus conditioned amygdaloid regulation of drives like hunger can shed some light on the recent debate about the Food Reward Hypothesis of obesity.  Stephan Guyenet has cited compelling evidence for the FRH, based on the  observation that rats fed a “cafeteria diet” of highly palatable junk food became fatter than rats fed calorically matched standard bland rat chow.  Merely adding flavor or flavor variety to the chow also resulted in fatter rats.

However, in an earlier post, “Does tasty food make us fat?“,  I argued that Guyenet’s version of the FRH suffers from two logical flaws:  First, Guyenet does not take a clear position on whether “reward” is an inherent property of foods, or rather a learned or conditioned property, relative to individual and cultural experience.  Second, while rewarding food is associated with obesity, the causal sequence can be questioned.  I think it is likely food reward is the is the consequence, not the driver of psycho-metabolic dysregulation.  Food becomes rewarding only after primary hypothalamic regulation becomes impaired, for example by the way that the particular fats and sugars in junk food desensitize hypothalamic receptors to insulin or leptin, as I described in “Obesity starts in the brain“.   Of course, once the amygdaloid food reward circuits are established, they can be expected to perpetuate an increased appetite and shift away from fat mobilization to fat storage.  But the amygdaloid reward circuit is not the primary defect — that remains the impairment to the hypothalamus.  The proof is that it is not just appetite that is impaired — it is also the metabolic consequence of a more active lateral hypothalamus and inhibited ventromedial hypothalamus.   If the hypothermic defect is repaired, the food reward circuit should extinguish.

THE BOTTOM LINE

Hormesis and the hypothalamus.   So how do we use this information?  Specifically, how do we “judiciously” apply “stress”s to re-program our limbic control system. What if we are gaining weight due to both a strong appetite and more “efficient” storage. Or what if we have trouble falling and staying asleep?  Or (more speculatively) what if we want to become more or less aggressive, or more or less sexually motivated?

In short, our understanding of the limbic system suggestions two approaches:

1.  Direct reprogramming of the hypothalamus. Every drive is regulated by a balance of stimulatory and inhibitory neurons.  By the logic of hormesis, we can stimulate the growth of one set of neurons or the other by periodically  ”starving” them of their normal stimuli, allowing a compensatory up-regulation of receptor neurons.  Often this process is slow, and the compensating adaptations may take weeks or longer — but with sustainable results. This is the reverse logic illustrated in several posts.

• “Change your receptors, change your set point”  demonstrates how exposure to uncomfortable stresses such as intermittent fasting, strenuous exercise, cold showers and the like can up-regulate dopaminergic neurons and thereby counteract conditions such as obesity, addiction and depression.  While the research cited in that article doesn’t specifically locate the dopamine neurons, , we know they have a high density in the hypothalamus, amygdala and other limbic structures, and the PET scans indicate a brain location consistent with the hypothalamus and amygdala.
• “A cure for insomnia?” describes the use of Sleep Restriction Therapy (SRT).  By forcing extended wake cycles, there is an apparent rebalancing of hypothalamic neurons in the ascending arousal system, thereby activating sleep-active neurons in the ventrolateral preoptic nucleus (VLPO) associated with the  “flip-flop switch” that produces distinct sleep-wake states.  As a result, SRT reduces the  excessive production of corticotropin-releasing factor (CRF) that is associated with many cases of insomnia.

Where does obesity begin?  What drives you to eat too much or expend too little energy, and why has there been such a dramatic increase in obesity since 1980? Some recently popular explanations are the carbohydrate / insulin hypothesis (CIH), singling out the prevalence of carbohydrates in the diet, and the food reward hypothesis (FRH), putting the primary blame on the availability of “hyper-palatable” food.

In this post I will present evidence for new paradigm, which I call the  Hypothalamic Hypothesis (HH).  I think it provides a better explanation for the facts of obesity than the CIH and FRH theories, and leads to some different advice about how best to lose weight.

Some recent research suggests that obesity starts with specific physical changes to the brain. Appetite is regulated by the hypothalamus, particularly the arcuate nucleus (ARC), ventromedial hypothalamus (VMH) and lateral hypothalamus (LH). It turns out that two very specific changes to the brain cause us to get get hungry, overeat, burn less fat, and gain weight. And these changes to particular brain structures come about as a result of what you eat, eating frequency, and to some extent your activity level. The problem of obesity or overweight is often portrayed as a single problem, but it is really two problems, and each type of obesity corresponds to one type of brain alteration. Failure to distinguish these two types of obesity has resulted in much confusion. In part, the confusion comes about because these two types of obesity frequently occur together in the same individual, although one type is usually dominant. If you understand this, and you understand the role your brain plays, you can become more successful at losing excess weight.

I’ll spend a little time explaining the theory, provide some specific suggestions for how it can help you fine tune your weight loss program, and try to point out why I think the Hypothalamic Hypothesis overcomes some weaknesses of the other obesity theories.

Two types of obesity.  One major type of obesity is subcutaneous (SC) obesity.  The man on the right is a Sumo wrestler with subcutaneous obesity,  but you don’t have to be a wrestler to have this type of fat distribution.  It is characterized by lots of looser, softer fat hanging from the torso, arms, legs and even the face.  A double chin and skin folds under the arms are not uncommon for this type.  SC obesity is more common among women than men.

The second major type of obesity is visceral or “intra-abdominal” (IA) obesity. This is depicted by the classic “beer belly” sported by the main in the left photograph, characterized by a protuberant gut, but frequently not a lot of extra fat on the legs or arms. It’s quite prevalent among men, but seen on many women as well.

The above photos show extreme types, but it is common for both types of obesity to coexist in the same person, in varying degrees.  Those with predominant IA obesity are sometimes referred to as “apples”; those with predominant SC obesity are called “pears”.

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Different metabolisms. The difference between subcutaneous and intra-abdominal obesity is not merely a matter of how adipose tissue is distributed on the body, but also about the biological composition of the fat tissue and it’s metabolic activity.  Subcutaneous fat is located just beneath the skin, and on the outside of the muscle tissue, all over the body.  By contrast, intra-abdominal fat– also called visceral fat–is located underneath the visceral muscles, deep within the gut.  It  surrounds the digestive organs — the liver, pancreas, stomach and intestines.  The difference can be seen clearly in the CT scans at the left.  The top image shows a cross-section at mid-belly level of someone with SC obesity, with most of the dark gray fat mass located right under the skin but outside the lighter grey visceral muscles and internal organs.  The bottom image is a similar CT scan of someone with IA obesity, showing much less subcutaneous fat, but considerable fat beneath the walls of the viscera, packed around the intestines.

What is important to realize is that the adipose tissue stored inside the abdomen is biochemically and metabolically very different than the fat stored right under the skin.  Both are called “fat” or “adipose tissue” but they behave as if they were entirely different substances. The image below at left is a micrograph of SC fat; the image at right shows IA fat cells.  Notice the different shape and size, but also the substantial dark “mortar” between the IA fat cell “bricks”.

The adipose tissue in IA fat is not an inert storage tissue.  On the contrary, it is a metabolically active hormonal “organ”: it is infiltrated by macrophages and secretes “adipokines” like interleukin-6, tumor necrosis factor alpha, and C-reactive protein.  These compounds are inflammatory signaling agents, associated with insulin resistance, diabetes, hypertension, and cardiovascular disease characteristic of Metabolic Syndrome.  The health effects of this inflammatory process have been the subject of intense study.  In this article, however, I’ll address only the role that these inflammatory processes have in the development of obesity.

The appetite center.  To understand the dynamics of each type of obesity, it is important to understand how appetite and body fat are governed by the brain. The hypothalamus regulates biological drives, including feeding, sleep and hunger.  As shown in the diagram at right (and also in this video) appetite, feeding behavior and metabolic rate are regulated by two sets of neurons that have opposite effects on appetite and metabolism:

• The  ”anorexigenic” POMC/CART neurons that inhibit appetite and increase the rate of fat oxidation in the body.  In response to nutrients and certain hormones, these neurons produce the appetite-suppressing neuropeptides propio-melanocortin, cocaine-and-amphetamine-regulated transcript and α-melanocyte stimulating hormone (α-MSH). The α-MSH binds to and activates secondary melanocortin-4 (MC-4) neurons in the ventromedial hypothalamus (VHM), causing satiety and increasing energy expenditure and  fat oxidation in the body. Animals with damaged or lesioned POMC/CART neurons eat voraciously and become obese.  Both leptin and insulin are potent hormonal stimulators of the POMC/CART neurons.  These neurons have receptors for appetite suppressing signals like insulin and leptin; low levels of either hormone will increase appetite and reduce metabolic rate. If  a deficiency of leptin or insulin persists, it will lead to obesity.
• The  ”orexigenic” NPY/AgRP neurons that stimulate appetite and slow down fat oxidation in the body.  These neurons produce two neuropeptides — neuropeptide Y (NPY) and agouti-related protein (AgRP) which act to inhibit α-MSH from binding to and activating the MC-4 satiety neurons and stimulates melanin-concentrating hormone (MCH) in the lateral hypothalamus (LH). This inhibition of MC-4 and stimulation of MCH enhances appetite and decreases metabolism and energy expenditure, conserving fat.  Animals in which the NPY/AgRP neurons have been damaged or destroyed by lesions become anorexic and lose weight.  Insulin and leptin inhibit the NPY/AgRP neurons, whereas the “meal timing” hormone ghrelin, which cyclically ebbs and flows, stimulates them.

These two sets of neurons govern fat gain and fat loss.  They effectively sense the energy status of body by centrally integrating inputs from a large number of circulating nutrients, neuropeptides and hormones, and they respond by outputting neuropeptides that drive behavior and peripheral metabolism. When they are in balance, a normal and healthful level of body fat is maintained, but when the balance of  orexigenic or anorexigenic signals shift, this adjusts the body’s fat and activity set points up or down.  As a prime example, if leptin levels in the hypothalamus are low, either because of low body weight or because the leptin is blocked from reaching its receptors in the POMC neurons, appetite will increase, fat oxidation will decrease, and this will lead to an increase in adiposity.

Insulin, leptin and appetite. There are two hormones which predominantly regulate body fat:  insulin and leptin. In healthy individuals, as Byron Richards describes,

Leptin uses adrenaline as a communication signal to fat cells, telling them to release stored fat to be used for fuel. This takes place in the course of a normal day between meals and at night during sleep…A drop in leptin signals hunger. Food intake stimulates insulin release. As a person eats, insulin is always directing some amount of triglycerides to go over to white adipose tissue and enter fat cells….This turns on the production of leptin in fat cells, causing the blood level to rise in response to the meal. As the leptin levels rise high enough, they signal to the brain that enough has been eaten. Leptin now signals the pancreas to stop making insulin…In overweight people, the communications involving insulin and leptin are inefficient. It is like making a phone call where no one answers. Insulin and leptin resistance mean that the hormones don’t communicate efficiently in response to food.” (The Leptin Diet, p. 13, 17, 23, 36)

Increased basal levels of either of these two hormones indicates increased energy stores and adiposity. The hormones have different metabolic effects depending on their site of action.  As Lustig explains, the action of these hormones “centrally” — inside the brain — is entirely different than that in the “periphery” — the rest of the body:

Insulin also plays a pivotal role in the control of appetite and feeding. In addition to its well-defined peripheral role in glucose clearance and utilization, insulin is involved in the afferent (and efferent) hypothalamic pathways governing energy intake, and in the limbic system’s control of pleasurable responses to food. Whereas insulin drives the accumulation of energy stores in liver, fat, and muscle, its role in the CNS tends to decrease energy intake. This is not a paradox, but rather an elegant instance of negative feedback. When energy stores abound, circulating insulin tends to be high; high CNS insulin tends to decrease feeding behaviors, thereby curtailing further accumulation of energy stores. Insulin’s central effects on energy intake are manifested in two complementary ways: first, insulin decreases the drive to eat; second, insulin decreases the pleasurable and motivating aspects of food.

This self-limiting regulatory action of insulin is also noted by Banks:

Insulin plays many roles within the CNS. Several laboratories have shown that some of the CNS effects of insulin are the opposite of those effects mediated through peripheral tissues. In particular, CNS insulin increases glucose and inhibits feeding, whereas serum insulin decreases glucose and increases feeding. Thus, to some extent, insulin acts as its own counterregulatory hormone, with CNS insulin producing features of insulin resistance.

Both insulin and leptin have an appetite suppressing effect when an elevated level of either one reaches the appetite center of the brain, specifically the satiety-inducing POMC/CART neurons within the arcuate nucleus (ARC) of the hypothalamus.  While similar in their appetite suppressing effect, insulin levels fluctuate in response to the ingestion of meals, especially carbohydrate-rich meals, whereas leptin levels generally reflects longer term changes in energy stores.   Most noteworthy for this discussion, however, these two hormones reflect the two different types of fat.  According to Woods et al:

Insulin is secreted in proportion to visceral fat, whereas leptin reflects total fat mass and especially subcutaneous fat. This is an important distinction with regard to the message conveyed to the brain, since visceral fat carries a greater risk factor for the metabolic complications associated with obesity than does subcutaneous fat. Elevated visceral fat carries an increased risk for insulin resistance, type 2 diabetes, hypertension, cardiovascular disease, and certain cancers. Hence, leptin and insulin each convey specific information to the brain regarding the distribution of fat, and the combination of the two additionally conveys information as to the total fat mass of the body.

Interestingly, Woods also reports the brains of females are more sensitive to leptin than insulin, whereas the reverse is true in mails, and that estrogen mediates this difference.   According to  Cnop el at., women on average have three times as much leptin as men, even after controlling for comparable degrees of body mass and insulin resistance. Which explains why there are more male “apples” and more female “pears” — though of course both types of obesity are represented to varying degrees in both genders.

While the appetite regulating actions of insulin and leptin within the brain are well known, what is less well known is that these the two hormones also use “remote control” from within the brain to activate fat loss in the rest of the body.  According to Woods:

As previously mentioned, when leptin is administered into the brains of experimental animals, there is a selective reduction of body fat, with lean body mass being spared. Likewise, when insulin is administered into the brain, there is a reduction of the respiratory quotient, suggesting that the body is oxidizing relatively more fat. These observations suggest that one action of these adipose signals within the brain is to reduce body fat, and a corollary of this is that fat ingestion would be expected to be reduced as well. Consistent with this, we have observed that when insulin is administered into the third cerebral ventricle of rats, fat intake is selectively reduced. Hence, it is reasonable to hypothesize that leptin and insulin, acting in the brain, reduce body fat by increasing lipid mobilization and oxidation and simultaneously by reducing the consumption of dietary fat.

In short, if you want to control your appetite and burn fat faster,  you want leptin and insulin to get inside your brain!  The problem in obesity is that these hormones are not adequately reaching and communicating with the appetite center of the hypothalamus.

Putting up resistance.  So far, I’ve described how leptin and insulin work to homeostatically regulate appetite and body fat in normal individuals.  But this carefully balanced feedback system becomea derailed in obesity.  There are some interesting, but fortunately rare, genetic or disease conditions where the leptin or insulin sensitive receptors in the hypothalamus become defective and insensitive to leptin or insulin. In other words, the “off” switch for appetite stops working correctly.  Or where the leptin or insulin molecules themselves are mutated or damaged and are thus unable to turn off the appetite switch.  Animals or humans with these defects eat voraciously, insatiably and become extremely obese. These rare cases provided some of the initial evidence for the current understanding of how leptin and insulin regulate appetite and body weight.

But defective  hormones and receptors are rare and do not explain the vast majority of cases of obesity. The “normal” cause of obesity involves involves leptin resistance or hypothalamic insulin resistance, whereby there is plenty of leptin or insulin circulating in the bloodstream, and the appetite-suppressing POMC neurons are functional, but not all of the hormone is reaching the receptors in the hypothalamus. The messenger is yelling, but the ears hear the message faintly.  There is a barrier or impediment between messenger and receiver.   The result in each case is that appetite is not getting satisfied, so there is a drive to overeat.  And furthermore, as Woods notes, the “remote control” fat burning functions of the hypothalamus are also reduced.  As a result, with more eating and less fat mobilization and oxidation, you get fatter.

Now, let’s see in more detail what happens to the hypothalamus in each main type of obesity.

Subcutaneous (SC) obesity and the brain.  Leptin is produced in adipose tissue, but specifically in SC fat.  The more SC fat, the more elevated the leptin concentration in the blood.  Normally this would provide a negative feedback signal, inducing satiety in the hypothalamus and increasing the release of fatty acids from fat cells.  In SC obesity, however, only a low level of this leptin is reaching the hypothalamus, so appetite and eating are not inhibited.  But why does this happen?  What is the mechanism?

Some, like Lustig, see insulin resistance in the brain as a likely driver of leptin resistance:

Hyperinsulinemia itself may be a cause of leptin resistance. As described, insulin and leptin use many of the same neurons, the same second messengers, and the same distal efferents to effect induction of satiety….Although confirmation in animal studies is needed…CNS insulin resistance may be a proximate cause of leptin resistance, promoting continued weight gain.

However, it is not plausible to blame leptin resistance on insulin resistance, because many of the obese are insulin sensitive.  For example, Sumo wrestlers notably  can weigh 500 pounds or more,  but they are typically insulin sensitive, and have low cholesterol. According to an study by  Gerald Reaven of Stanford:

The ability of insulin to mediate glucose disposal varies more than six-fold in an apparently healthy population, and approximately one third of the most insulin-resistant of these individuals are at increased risk to develop cardiovascular disease. Differences in degree of adiposity account for approximately 25% of this variability, and another 25% varies as a function of level of physical fitness. The more overweight/obese the person, the more likely they are to be insulin-resistant and at increased risk of cardiovascular disease, but substantial numbers of overweight/obese individuals remain insulin-sensitive, and not all insulin-resistant persons are obese.

Recent evidence suggests that the crux of leptin resistance can be located at the door to the brain:  the blood-brain barrier (BBB).  The BBB is semipermeable along the arcuate nucleus.  This allows for controlled, selective transport of various nutrients and energy signals.  According to Banks,

The blood–brain barrier (BBB) prevents the unrestricted movement of peptides and proteins between the brain and blood. However, some peptides and regulatory proteins can cross the BBB by saturable and non-saturable mechanisms. Leptin and insulin each cross the BBB by their own transporters. Impaired transport of leptin occurs in obesity and accounts for peripheral resistance; that is, the condition wherein an obese animal loses weight when given leptin directly into the brain but not when given leptin peripherally. Leptin transport is also inhibited in starvation and by hypertriglyceridemia. Since hypertriglyceridemia occurs in both starvation and obesity, we have postulated that the peripheral resistance induced by hypertriglyceridemia may have evolved as an adaptive mechanism in response to starvation.

In a study on mice, Banks et al. showed  that triglycerides, but not free fatty acids, induce leptin resistance.  This same study showed that, that fasting for 16 hours reduced triglycerides and increased leptin transport, whereas fasting for 48 hours increased triglycerides and impaired leptin transport. This provides support for intermittent fasting as a strategy to reverse leptin resistance.  Elevated triglycerides also enhance the transport of ghrelin, the hormone responsible for initiating feeding at conditioned meal times, which explains why certain obese people get especially hungry around meal time.

Triglyceride levels tend to increase with your degree of adiposity.  But what causes them to rise in the first place?  The primary culprit seems to be fructose, which is converted to triglycerides if consumed in excess. Of course, fructose is part of sucrose and high fructose corn syrup, so any of these sugars in excess will elevate triglycerides, cause leptin resistance, and SC obesity.  Foods containing high concentrations of sugar include  sodas, candies, breakfast cereal, bread and other baked goods, but also sugary fruits like bananas, mangos and raisins. Michael Eades recognized the connection between triglycerides, the blood brain barrier and appetite in his 2007 blog post “Leptin, low-carb and hunger“. But I suspect that it is specifically the effect of fructose reduction — and not the generalized carbohydrate reduction postulated by Eades– that is the primary explanation for low carb diets work to reduce appetite so well for many people.

Diet, of course, is not the only factor affecting how the blood-brain barrier affect leptin resistance.  For example, Banks also notes that epinephrine enhances leptin transport across the BBB by a factor of 2-3 fold.  This explains why exercise and excitement can act to suppress appetite.

Intra-abdominal (IA) obesity and the brain.  Insulin is produced by the pancreas, when it circulates through most of the body outside the brain and spinal cord — what physiologists call the “periphery” — it’s main function is to regulate the availability and storage of glucose and fatty acids, thus preventing excessive glucose or fatty acid levels in the bloodstream.  When insulin receptors in liver, muscle, and other tissues become less responsive to insulin, the resulting insulin resistance results in hyperinsulinemia and its associated metabolic derangements such as Type 2 diabetes. There has been much investigation regarding what causes insulin resistance, the lead hypothesis being some sort of inflammation due to many suspects, including certain fats.

Unlike leptin, triglycerides do not impair insulin transport into the brain. According to a study by Urama and Banks,

[T]he triglyceride triolein significantly increased the brain uptake of insulin, an effect opposite to that on leptin transport, in starved obese mice….That is, leptin transport across the BBB increased with short-term fasting but decreased with starvation and with administration of triolein. In contrast, insulin transport is decreased by short-term fasting but increased by starvation and by triolein.

So what, if not triglycerides, leads to insulin resistance in the brain?

The answer appears to be: free fatty acids. Certain fatty acids – trans fats, certain long-chain saturated fatty acids, and omega-6 unsaturated fatty acids  – produce an inflammatory response in insulin receptors that blunts insulin sensitivity. By contrast, other fatty acids — principally omega-3 fatty acids (like flax or fish oil) and short or medium chain triglycerides (like coconut oil) — are actually anti-inflammatory).  Certain sugars like fructose also appear to be pro-inflammatory.  But what has not been recognized until recently is that these inflammatory processes occur not just in the liver and muscles, but also within the hypothalamus.

And in fact, inflammation of the hypothalamus may be where insulin resistance starts.

Posey et al found that mice fed a high fat diet, with equal calories to a low fat diet, gained 60% more adipose tissue than those on the low fat diet.  Other experiments by Kaivala et al. showed a high fat diet resulted in a 60% reduction in CNS insulin levels, inversely associated with changes in body weight. Thaler et al. , Schwartz et al and Benoit et al. showed that  one particular long chain saturated fatty acid — palmitic acid — causes inflammation and reduces insulin sensitivity in the hypothalamus, leading to overeating and obesity.  Arruda et al. found that intracerebroventricular  injection of an inflammatory cytokine (TNF-α) or stearic acid (another long chain saturated fatty acid) into lean rats induced insulin and leptin resistance in the hypothalamus and hyperinsulinemia and down regulated thermogenesis and oxygen utilization.  In TNF knockout rats (those missing the TNF receptor), the TNF-α did not produce any of these effects, and the rats were protected.  Furthermore, Araujo et al showed that co-administrering an anti-inflammatory drug (infliximab) restored normal oxygen consumption in the obese rats.  Similar results from other studies have been reviewed by Schwartz et al .

Interestingly, high levels of fructose can also cause inflammation and insulin resistance, leading to IA obesity.  If you are lean and healthy, fructose at reasonable levels is converted to glucose in the liver, and brief excess is then stored as glycogen in the liver and muscles.  But in vast excess, fructose is converted to fat of two types — triglycerides and one particular fatty acid.  Can you guess which fatty acid?  The answer is palmitic acid, the fatty acid associated with brain insulin resistance. The liver begins to accumulate the excess fat – a condition known as steatosis or fatty liver disease — which results in hepatic insulin resistance.   So while high fructose consumption causes elevated triglycerides, those triglycerides cause leptin resistance and are not a direct cause of insulin resistance. do not cause insulin resistance, only So it looks like fructose (and of course sucrose which is 50% fructose) is involved in the genesis of both SC obesity and IA obesity.  The fact  is just one manifestation of how easy it is to get confused about “the cause” of obesity.  Because there are two types of obesity with different but intertwined etiologies, the logic of obesity is not always so easy to sort out.  But the various diveres causal threads always come together in the arcuate nucleus of the hypothalamus

What is most illuminating, however, is research by Ono et al showing that hypothalamic insulin resistance precedes — and probably causes — insulin resistance in other organs and tissues.  Ono found that feeding rats a high fat diet induced insulin resistance in the hypothalamus after only one day, with no concurrent hepatic insulin resistance!  It took a full 3 days on this diet for insulin resistance to show up in the liver, and 7 days for the muscles and peripheral tissues to become insulin resistant.   The mechanism of inflammation was the activation of the mTOR/S6K pathway by exposure to fatty acids.  The S6K protein apparently inhibits insulin signaling in the arcuate nucleus of the hypothalamus, activating the orexigenic NPY/ArGP neurons and inhibiting the POMC neurons.  Similarly, Pagotta has marshalled other evidence suggesting that insulin resistance starts in the brain.  Of particular note is a study by Obici et al, in which central administration of insulin suppressed glucose production by the liver, and blocking insulin signaling in the brain impaired the ability of insulin to inhibit glucose production in the liver. Finally, an excellent post by Stephan Guyenet cites a similar study by Morton and Schwarz showing much the same thing.  As Guyenet notes,

Investigators showed that by inhibiting insulin signaling in the brains of mice, they could diminish insulin’s ability to suppress liver glucose production by 20%, and its ability to promote glucose uptake by muscle tissue by 59%.  In other words, the majority of insulin’s ability to cause muscle to take up glucose is mediated by its effect on the brain.  

In regard to insulin signalling,  the brain seems to be in charge of the liver.  And this plays out in the genesis of insulin resistance.

This raises an interesting question:  why would insulin resistance start in the brain, rather than the liver or the muscles?  When you think about it for a few minutes, it actually makes sense.  The hypothalamus is the ultimate arbiter of whether or not the body has adequate energy intake. It does this by homeostatically regulating energy stores and energy balancing hormones. In the case of leptin resistance, as we’ve already seen, the brain acts to restore homeostasis signaling the peripheral metabolism to “grow” more subcutaneous fat (by increasing appetite and slowing fat oxidation).  If insulin signaling in the brain is blocked or impaired, homeostasis requires the initiation of compensatory processes that will bring more insulin into the brain.  But how to do that?  Insulin is not produced in the fat cells, so growing more fat won’t directly help.  To do this, the periphery must become somehow become hyperinsulinemic, in order to overcompensate so that enough insulin gets into the hypothalamus.  And the best mechanism for this is to induce whole body insulin resistance, primarily in the liver and muscles.

But how does the insulin resistant brain orchestrate insulin resistance in the periphery?  The answer, apparently, is to grow intra-abdominal fat. As Ljung notes, hypothalamic insulin resistance disrupts the hypothalamic-pituitary -adrenal axis (HPA), leading to increased secretion of ACTH and cortisol.  These hormones in turn stimulate the growth of intra-abdominal adipocytes.  The IA fat proliferates macrophages and releases pro-inflammatory  fatty acids and “adipokines” into the bloodstream. (See “Intra-Abodominal Adipose Tissue: The Culprit?“) The portal circulation carries these to the liver where they promote steatosis (fatty liver), insulin resistance, and local inflammation. The systemic circulation further carries these fatty acids and proinflammatory molecules to skeletal muscle where they promote lipid accumulation, insulin resistance, and local inflammation.  As Ross showed,  it is IA fat, not total fat or SC fat, that is associated with whole body insulin resistance.  Insulin resistance in the body causes the pancreas to go into overdrive to supply more insulin, resulting in hyperinsulimia. As basal insulin levels increase, the hypothalamus is now getting its fix of insulin, keeping hunger in check.  Of course, the level of IA obesity and hyperinsulimeia will only be what is required to handle the degree of inflammation experienced by the arcuate nucleus in the brain.  One this inflammation is reduced or removed, and the NPY/AgRP neurons become more sensitive to insulin, the requirement for elevated basal insulin should go down, and with it the need for intra-abodominal fat.

In slogan form, here is the Hypothalamic Hypothesis of Obesity:

If the hypothalamus is deficient in leptin, it directs the body to grows more subcutaneous fat.

If it is deficient in insulin, it directs the body to grow more intra-abdominal fat.

Now for some practical advice:   How can you use the Hypothalamic Hypothesis to lose unwanted fat or better control your weight?

1.  Start by assessing your degree and type of adiposity.  Do you have a waist-to-hip ratio greater than 0.8 (women) or 1.0 (men) and carry your extra weight a belly that sticks out in front? That’s IA fat and you are a probably an  ”apple”. Or do you have a waist-to-hip ratio of less than 0.8 (for women) or 1.0 (for men) and carry most of your extra weight on your butt, your thighs, chest, and possibly also your arms and neck?  That’s SC fat and you are probably a “pear”.   Of course, you may be an “apple-pear” and carry extra fat in both locations, but it is good to know which type of fat is dominant.  If you want a much more precise assessment using specific measurements of body weight, height and other body dimensions, I recommend consulting “Assessing Your Risk”, Chapter 9 in Protein Power, by Eades and Eades.

2.  If you are primarily a “pear”, and particularly if you are significantly overweight, you are leptin-resistant.  Your primary focus should be on reducing triglycerides.  Largely, this means cutting back on carbohydrates with fructose or sucrose (which is a disaccharide of fructose attached to glucose) is readily converted to triglycerides by the liver.  And it is triglycerides that primarily induce leptin-resistant SC obesity.  So of course you want to cut out soft drinks, cookies, cakes, ice cream, candies, most fruits, and most breads (except those with no sugar, which are hard to find). But so long as you are reasonably insulin sensitive, you don’t have to cut out starches.  Potatoes and rice are probably fine if you are insulin-sensitive as long as you avoid any sugar in the same meal.  If you are an “apple-pear” and are resistant to both leptin and insulin, then you can still eat fructose-free starches like potatoes and starch, but you must not add any pro-inflammatory fats. The question of what constitutes a “pro-inflammatory fat” is a controversial one.  Some fats, such as trans fats and high levels of omega-6 fats are clearly pro-inflammatory, while omega-3 fats, mono-unsaturates like olive oil, and medium chain triglycerides like coconut oil are anti-inflammatory.  But for saturated fats, the picture is less clear and the studies are all over the place.  Probably some saturated fats are OK.  But some people have found that cutting back on cheese and nuts help them shed abdominal fat.  Milk and butter from grass fed cows may be preferable to that from grain fed cows.

What about alcohol?  Alcohol is frequently assumed to raise triglyceride levels, but observational studies show this may not necessarily not true.  Moderate alcohol may actually reduce triglyceride levels.

Finally, as the Banks’ fasting study suggests, intermittent fasting (16 hours, but not 48 hours) can reduce triglycerides and restore leptin sensitivity.

3.  If you are primarily an “apple”, pre diabetic, or trying to lose stubborn belly fat — the last 10-20 pounds,  your primary focus should be on eating a non-inflammatory diet.  For the most part, this means cutting back on certain fats — trans fats (anything “partially hydrogenated” on the nutrition label), vegetable fats high in omega-6 oils, and perhaps certain saturated fats like those in meat, milk, butter or cheese from grain-fed cows. As mentioned above, the question of which saturated fats are “pro-inflammatory” is controversial. The strongest evidence that connects saturated fatty acids to brain insulin resistance is for palmitic acid, but that does not mean all saturated fatty acids cause insulin resistance. In any case, don’t shun non-inflammatory fats like fish oil, olive oil, or coconut oil.  Adding these to your meals can help reverse IA obesity.  I’ve personally found coconut oil to be great for energy and weight loss.

Because consuming high levels of sugar in the diet (fructose, sucrose or syrups that contain them) causes output of pro-inflammatory palmitic acid,  foods containing sugar should be restricted.  If you are lean and have a have a healthy liver, I see nothing wrong with fructose in moderate quantitates.  The daily apple will not hurt you, but the excessive amounts of sugar in  sodas, pastries, ice cream, bread (which contains sugar)  sweet fruit — make you (or maintain you as)  both a  ”pear” and an”apple”.

In addition to avoiding high levels of certain fatty acids and sugars, inflammation can also be reversed by a few additional steps:

• ensuring adequate intake anti-inflammatory micronutrients such as Vitamin D and magnesium
• high intensity exercise, intermittent fasting, cold showers and other hormetic stressors which upregulate anti-inflammatory brain compounds such as BDNF

Caveats. In making the above suggestions, I would like to make a disclaimer:  This post is primarily about a new paradigm of obesity, but I realize that people are looking for specific dietary recommendations.  The  above dietary advice is based upon my best attempt to interpret two general principles regarding the effects of triglycerides and inflammation on the appetite center of the hypothalamus.  In doing this, I am relying on a large body of empirical evidence that is sometimes ambiguous or contradictory — for example, regarding which saturated fats are pro-inflammatory, and which are protective.  And so I may be wrong about the hypothalamic effect of this or that specific food.  Despite this uncertainly, the HH provides a test for deciding whether a food or practice is obesogenic and leads to overeating: namely whether it raises triglycerides or inflames the hypothalamus.  And it is also apparent that these guidelines for foods to avoid cut across conventional macronutrient categories like “fat” and “carbohydrate”, since the hypothalamus does not sort things out that way.

…

OTHER THEORIES OF OBESITY.  I would like to close by contrasting the Hypothalamic Hypothesis with two other theories of obesity, showing how it better accounts for certain facts, and leads to perhaps some different recommendations for losing excess body fat.

The Carbohydrate / Insulin Hypothesis (CIH).  Most prominently advocated by Gary Taubes, CIH holds that dietary fat plays no role in obesity.  Rather, dietary carbohydrates, through their stimulation of insulin secretion, result in a greater degree of fat storage. Carbohydrates drive insulin drives net fat storage. Obesity is a disorder of excess fat accumulation, not overeating or inadequate energy expenditure.  In its favor, CIH can account for the close correlation between obesity and hyperinsulinemia, and the success of low carb dieting.  However, it manifestly does not explain why many obese people, like Sumo wrestlers, are insulin sensitive, with normal insulin levels and no indications of diabetes, cardiovascular disease, or other signs of Metabolic Syndrome.  It also does not account for why others, such as the Kitavans and Okinawans, can  eat a diet low in fat but high in certain starchy carbohydrates (polymers of glucose) like root vegetables or rice, and remain lean, with low basal insulin levels.  And it cannot explain why, despite sincere attempts, many people can lose only a certain amount of weight (probably subcutaneous fat) on low carb diets, but often stall and remain insulin resistant when continuing to eat a high fat / low carb diet.  The HH can explain all these facts by carefully distinguishing SC obesity from IA obesity, and by narrowing the cause of type of obesity to very specific types of carbohydrate (fructose and sucrose) and fat (long chain saturates, trans fats and omega-6 fats).  And, perhaps heretically, HH predicts that once you’ve maxed out the benefits of low carb, you can get rid of that paunch and insulin resistance by cutting back on fats– at least the pro-inflammatory fats.

The CIH also cannot explain certain anomalies such that described by Stephan Guyenet and Chris Masterjohn:  the LIRKO mouse which has severe hepatic insulin resistance and hyperinsulinemia — but remains leaner than its normal counterparts.  Guyenet and Masterjohn seem to conclude from this that insulin resistance cannot be a cause of obesity.  The mistake they make, I believe, is overlooking the possibility that only one type of insulin resistance — that of the hypothalamus — leads to obesity.  The LIRKO mouse they discuss had an insulin resistant liver, but apparently a well functioning hypothalamus.  It would have been interesting to feed it some pro-inflammatory fats to see what would happen.

One further aside about the CIH:  I must admit that I was previously persuaded by the orthodox version of CIH and it’s explanation about hunger–which I now suspect is incorrect.  I employed this theory elsewhere in this blog to explain the appetite-suppressing effect of low carb diets, intermittent fasting, and flavor control diets such as the Shangri-La Diet.  The explanation was based on what I thought was a very plausible theory I first encountered in Gary Taubes’ Good Calories, Bad Calories, Chapter 24,”Hunger and Satiety.” .  The insulin-lowering effect of low carb diets is supposed to counteract hunger from hypoglycemia by making glucose and free fatty acids more available.  And the appetite inducing effects of  appetitive flavors or aromas is explained by their action (probably via the vagus nerve, mediated by the brain’s  tractus solitarus) in eliciting a preprandial insulin response.  This preprandial insulin response supposedly causes a sudden drop in  blood glucose, inducing hunger.   I now believe this theory is wrong, or at least incomplete, for several reasons.  Primary among those reasons are my own experience with blood glucose self monitoring, where I noticed that my blood glucose would typically drop after, but not before I would get hungry.  Also, preprandial insulin responses are typically fairly small and unlikely to reduce blood sugar enough to induce hypoglycemic hunger. So the preprandial insulin response seems too little, too late.  It is more likely an effect, not a cause, of hunger.  I now suspect that a more likely explanation would be the direct action of the vagus nerve and tractus solitarus on the orexigenic or anorexigenic neurons in the ARC, or on the permeability of the blood brain barrier.  But that will be a topic for another post.

The Food Reward Hypothesis (FRH).  The most effective advocate for the FRH is Stephan Guyenet, of Whole Health Source.  Guyenet is the first to admit he is not the originator of this theory, which is common among obesity researchers and was prominently featured in David Kessler’s book, The End of Overeating. And Stephan also takes a modest stance in stipulating that he takes “food reward” to a be a major explanatory factor, but not the sole causal factor, for obesity. For example, he mentions exercise, leptin resistance, energy excess and, yes, even hypothalamic inflammation, as “other” contributory causes to obesity. So FRH is not supposed to be a monocausal theory of obesity. But modesty aside, Guyenet has put a stake in the ground and marshaled considerable argument and evidence in support of FRH.  Briefly, FRH holds that feeding people (or animals) foods have a high “reward” level results in overeating and obesity.  Here is how Guyenet defines “food reward”:

I use the term food reward to refer specifically to the motivational value of food, i.e. its ability to reinforce behavior.  For example, acquiring a taste that causes a person to seek out the food in question more often.  This is how some, but not all, researchers define the term.  Others use the term “food reward” to refer to both the motivational and the palatability value of food.  Palatability refers specifically to the enjoyment derived from a food, also called its hedonic value.  Palatability and reward typically travel together, but not always. (“The Case for Food Reward,” Oct, 1, 2011)

The theory is supported by experimental evidence, for example by the rapid weight gain seen with rats switched from ordinary chow to a  high fat, high sugar “cafeteria diet”, and further developed by referring to the effects of such diets on brain opioids, dopamine circuits and other neurochemistry. Guyenet goes on to propose a remedy for the abundance of super palatable food:  just say no.  By avoiding overly rewarding food, our brains can return to sane eating and obesity can be avoided or reversed.

I feel a certain affinity for the FRH theory because, like HH, it is a “brain-centric” theory of obesity.  Guyenet’s self-described field of research is “neurobiology of body fat regulation and obesity”, which I agree is the most promising way to study of obesity.  I’ve been excited to follow his cogent summaries of the most interesting research in this field. However, the FRH seems to have incorrectly formulated the connection between the brain and obesity.  In fact, I’ve already discussed the FRH theory in another post, “Does tasty food make us fat?“.   Here is what I wrote there:

But I think the theory is wrong, for the simple reason that it too blindly takes correlation for causation. And in doing so, it gets the causal direction mostly wrong. We don’t get fat because food has become too tasty. Rather, to a large extent, it is the metabolism and dietary habits of the obese that make food taste too good to resist, leading to insatiable appetites. And the good news is that we are not consigned to blandness.  If we eat and exercise sensibly, we can eat flavorful, delicious foods and enjoy life, without packing on the pounds.

I had not formulated the HH theory when I wrote that post, but it fits the bill of what I said there: it is the metabolic effects of the pertinent foods in “cafeteria” diets that make them “rewarding” and engender the secondary effects on pleasure-related neurotransmitters like beta endorphin, dopamine or serotonin.  What HH does is to more specifically locate the primary metabolic effects within the arcuate nucleus of the hypothalamus, rather than elsewhere in the body.

I think that HH can explain a number of things that FRH cannot.  FRH is a somewhat vague in that it does not go very far to identify what specific attributes of food make them rewarding and what specific mechanism are involved.  Somehow, sugar, fat and salt are involved. It is more like a schema than a full theory, which makes it hard to test or criticize. By contrast, HH is very specific about the mechanisms by which specific food chemistries interact with specific parts of the brain.  HH,  unlike FRH, provides an explanation for why certain “rewarding” foods will eventually lead to  either subcutaneous obesity or rather intra-abdominal obesity.   HH holds that if you are neither leptin resistant or insulin resistant, then no foods will be inherently hyper-rewarding, at least initially.  Foods only become hyper-rewarding once insulin or leptin resistance begins to manifest itself.   HH makes the further prediction that very tasty, palatable foods that contain no fructose or sucrose (or other agents that elevate triglycerides) or pro-inflammatory fats, will not lead to obesity, no matter how good they taste.

A wider perspective: The homeostatic pleasure principle.  Finally, I think that the Hypothalamic Hypothesis provides a way to connect the hormonal regulation of obesity to something overlooked by both CIH and FRH:  the role of emotion and cognition in obesity, and the relation of obesity to our wider sense of well being.  Obesity is often a response to emotional factors like stress and depression, and conversely might be reversed by cognitive techniques such as cognitive reframing and meditation.  By locating the original of obesity within the hypothalamus, it becomes plausible to understand how stress hormones like cortisol and or calming neurotransmitters like serotonin can have a powerful and direct effect on the behavior of hypothalamic neurons and their sensitivity to leptin and insulin, since these neurochemicals are lurking nearby within the “neighborhood” of the brain.  Looked at more broadly, the hypothalamus can be thought of as a homeostatic regulation system that attempts to maintain an internal subjective sense of well-being or pleasure with respect to a broad range of drives, including not just eating, but sleep, sex, aggression, fear and other emotions.   This  homeostatic “pleasure principle” is fundamental — its provides a way to translate objective needs of the organism into conscious desires and emotions.  This fits into a related line of thinking about brain receptor sensitivity that I wrote about in my post “Change your receptors, change your set point“.  Whenever there is a dysregulation of the pleasure principle, such as occurs in the appetite drive of obesity, but also in conditions such as depression or addiction, we should look within the control system itself to find out what is going wrong. And that is what the HH does, by looking for specific brain mechanisms that explain not only our subjective experience, but the way the rest of the body responds objectively in homeostatic response to physiological disturbances.

Like this article or disagree with it?  Add you comments below, or join the more extended discussion in the Discussion Forum.

Many of the questions I get on this website and the forums are of this type.  People understand the general concept of hormesis, namely that exposure to controlled amounts of stress can be beneficial, because it elicits beneficial adaptive responses in the organism.  They understand that weight lifting builds muscles, and that intermittent fasting and calorie reduction can be healthful. But too much of any stressor — weight lifting, caloric restriction, sunlight, allergens  – can have adverse consequences.  With hormesis, it seems, the Goldilocks principle applies: to get a benefit, the level of stress must be “just right”.  And because it’s so easy to veer into overload, many people seek to avoid even mild stress:  Avoid allergens. Cover up with sunscreen. Eat frequent small meals. Don’t exert yourself. But if you choose this path, you forgo the possible hormetic benefits.

So how do you determine the optimum level and frequency of exposure to a stress?  And how much rest or recovery between exposures is optimal?

These are important questions, difficult to answer with certainty.  Of course, all over the Internet you will find those who tell you exactly how many days each week is optimal for lifting weights, how much sun tanning is safe or dangerous, what level of dietary carbohydrate or food restriction is optimal or unhealthy.  In some cases, they will cite studies to support their position. But there is one big problem with all this advice, even the advice based upon careful scientific studies:

Individual responses to hormetic stressors can vary significantly.

Just as responses differ between individuals, a given individual’s ability to tolerate and benefit from hormesis changes over time, and as a function of previous exposures to stressors.  This makes it virtually impossible to reduce hormesis to a simple formula. And yet, the situation may not be so hopeless.  There are actually some tools and metrics we can use to quantifiably determine whether hormesis is helping or hurting us, and thus to “adjust” the dose.

Allostasis. There is a general biological principle that can help us dial in the right level of hormesis.  The principle is called “allostasis”.  Most people are familiar with the related concept of homeostasis, the tendency of a system to maintain a constant internal state, such as the pH, temperature, or oxygen concentration of the blood, within a fairly narrow range.  This concept was developed by the famous nineteenth century biologist, Claude Bernard, who observed that organisms strive to control their internal environment, or milieu interieur, within tight physiological constraints, through physiological processes that resist disturbances from the external environment and quickly restore normal operating conditions.   This notion was later formalized by Walter Canon as “homeostasis”, the tendency of a biological system to regulate its internal environment within a stable range.

While the concept of homeostasis has some validity, in actuality it is of fairly limited application.  In fact, most biological systems do not self-regulate physiological variables within a narrow range, but tolerate a fairly wide range of variation.  During the course of a typical day, blood glucose and insulin levels rise and fall by as much as 50% or more.  Blood pressure, heart rate, and adrenaline surge upon waking and standing in the morning, and increase to further heights when engaging in vigorous exercise, or responding to threatening or emotional situations.

Bernard and Cannon developed the concept of homeostasis to apply only to regulation of the internal environment, particularly that of the cell or circulatory system. It was not intended to describe the external condition of organs or whole organisms.  Yet others have extrapolated this concept and applied it to the misleading notion of “set points”.  For example, some have advanced the idea that each of us is born with a body weight set point from which we can only deviate transiently and in a futile manner through diet and exercise, but which we are doomed to return to.  But body weight or body fat is not an “internally” regulated physiological variable, despite the efforts of some to tie this to the hormone leptin.  Rather, it is the result of a number of interacting systems, which frequently lead to a relatively stable output.  I’ve provided a more detailed critique of the set point concept in my post, Change your receptors, change your set point.

On the contrary, when you consider the whole organism, you are struck more by its variability over time than by its constancy.  Sterling, Eyer and McEwen have contrasted the stability of homeostasis with what they call “allostasis” or “stability through change”. “Stability” here does not mean a static state, but rather a dynamic physiological process which allows the organism to sustain itself in the face of external challenges.  For example, hormones like cortisol, adrenalin and catecholamines, and mediators like cytokines, allow us to adapt to changes in activity level. Digestive hormones like insulin and glucagon, and secreted digestive enzymes like proteases, amylases and lipases, allow us to effectively respond to the sudden ingestion of food, otherwise known as “meals”.  On longer time scales, major morphological changes in the overall shape and and size of the body allow animals to handle episodic changes like pregnancy, migration, or hibernation.  While organisms and physiology are stable enough to survive, they do not maintain or even strive for a state of constancy.

Allostasis, not homeostatsis, better describes how we deal with changing circumstances.

Changes which are beneficial in the short term to handle an external stress, may be harmful or pathological if maintained chronically.  So for example, glucocorticoid and catecholamine hormones such as cortisol and adrenaline are helpful, even essential, for gearing the body up to handle acute stress.  Without such hormones would we be unable to get up in the morning, much less deal with emergencies. But these same hormones become harmful or deadly when chronically elevated, causing significant damage to the cardiovascular system and neurodegenerative conditions such as depression and memory loss.  The “biphasic” effect of cortisol and other arousal hormones and catecholamines is encapsulated by the Yerkes-Dodson Law, illustrated in the figure at the right, which holds that performance increases with physiological or mental arousal, but only up to a point. When levels of arousal become too high, performance decreases.

Similarly, insulin, which is essential for the short term digestion of carbohydrates and protein, and for facilitating tissue growth, can likewise be harmful if elevated chronically, leading to obesity, cardiovascular disease, inflammatory diseases, and possibly cancer.  McEwen refers to the elevation of these stress related hormones and effectors as “allostatic load” and their chronic elevation as “allostatic overload”.

Hormones are neither good nor bad in and of themselves.  They are helpful at the right time and for the right length of time.

Alternating states and opponent processes.  I’ve written about opponent processes as an explanation for psychological adaption in my post on The opponent-process theory of emotion.  Here I would like to go further and generalize the opponent process theory to more broadly characterize our adaptive physiology.

Our natural allostatic variability typically manifests itself in an oscillation between two states or “extremes” which alternate or fluctuate over some characteristic interval of time that can range from seconds, to hours, days, months, or years.   These two states are often thought of as “high” and “low” levels of some variable hormone, enzyme or effector. But I think they are better considered merely as opposing conditions.  That’s because what appears to be “states” are really the results of underlying processes that move the organism in opposite directions — opponent processes. These processes typically come in pairs and act to balance each other, like yin and yang. It is important not to confuse the states and the opponent processes.  These alternating states are the resultant outcomes of the opponent processes; the visible “state” reflects the dominant process, but both processes are always in play to greater or lesser extents.

This concept of may be confusing, so here are a few examples of alternating states and associated opponent processes, with widely varying temporal scales. In each case “State A” exists when “Process a” dominates over “Process b”, and “State B” exists when process b dominates:

State A     State B            Process a        Process b                     Frequency

Eating      Fasting             Anabolism       Catabolism                    3-24 hrs
Waking    Sleeping           “C” process      ”S” process                   24 hrs
Exercise   Rest                Sympathetic     Parasympathetic            varies

Eating and fasting. You could attempt to characterize the A and B states as “active vs. passive”, “stressful vs. restful” or “bad vs. good” but that is not quite right. Take eating and fasting, for example.  You might argue that eating is the active or stressful state, because it places a demand on the digestive system, and the fasting period between meals allows the digestive system to recover.  However, if the fast is continued beyond a certain point, it becomes the stressor.  After about 12 hours, the stress of fasting causes a rise in catabolic “breakdown” processes, upregulates the neuroprotective hormone BDNF, and the process of autophagy activates the breakdown of intracellular materials to fuel the mitochondria. Utilized in moderation, the “stress” of fasting thereby activates beneficial processes that protect and defend us.  Once you resume eating, the “stress” of fasting is relieved and the anabolic “building” process kick in with the rise of insulin.  This has its own benefits, in repair and growth.  It is important to note that the anabolic hormones like insulin and the catabolic ones like glucagon or adrenaline are always present at some level; they never “go to zero”.  Yet one or the other is dominant at a given time, depending on the state of digestion.

Wake and sleep. Similarly, you could say that wakefulness is active and stressful, whereas sleep is passive and restorative.  But again, this would be misleading. Wakefulness and sleep are the outcome of a dynamic, alternating balance between two essential processes, the “C process” and the “S process”. The “C process” generates a wakeful state based upon activation of  the ascending arousal system, including cholinergic, noradrenergic, serotoninergic, dopaminergic, and histaminergic neurons located in the hypothalamus and other brain nuclei.  These neurons release corticotropin-releasing factor (CRF),  ACTH, and cortiosol on a regular diurnal cycle. This arousal system interacts with inhibitory “sleep-active” neurons in the ventrolateral preoptic nucleus (VLPO), releasing GABA and other sleep-inducing neurotransmitters.   These sleep promoting neutrons and neurotransmitters represent the “S” process. The result is a “flip-flop switch”  producing distinct sleep and wake states with abrupt transitions.  The “C” and “S” processes each never actually stop, but they continuously wax and wane, with one of the two becoming dominant and leading to either wakefulness and sleep. Even within the states of wakefulness and sleep there are many regular oscillating subcycles; for example REM sleep, deep sleep and light sleep. Disruptions in this process can lead to insomnia, and can be corrected by Sleep Restriction Therapy, as I’ve described in my post A cure for insomnia.

The reality is that for each basic physiological process we need both A and B states and the underlying a and b processes.  The opponent processes represent polarities of an indivisible “yin-yang” pair.  They balance each other, but not in a constant ratio.  The a and b processes cannot be indefinitely sustained, but each have within themselves the seeds of their own demise, by inducing their complementary, inhibitory process.  Biological organisms are constructed out of complementary and opposing physiological process, which naturally give rise to  an alternation between the A and B states.  This is a phenomenon I will refer to as stress oscillation.

Stress oscillation builds dynamic range.  So what does allostatis and the opponent processes have to do with hormesis?  Sometimes hormesis is thought of unidimensionally:  lift weights to build muscle.  Fast or reduce carbohydrates to lower insulin and reduce weight.

But in reality, hormesis should be thought of as a binary process of alternating stress and recovery.

Lifting weight builds muscles because it induces “catabolic” microtrauma to the muscles; it is the rest between workouts, in combination with adequate diet, that leads to the “anabolic” rebuilding of the muscle.  Both stress and recovery are necessary.  For the same reasons, weight loss through insulin lowering should be balanced with sufficient periodic insulin raising to maintain lean body mass, and maintain the healthy function of the insulin producing system, including the pancreatic secretory islets and the insulin receptors in the brain and muscle tissues.  One risk of an unremitting “insulin sparing” diet, such as a very low carbohydrate diet without periodic insulinogenesis is the induction of a state of physiological insulin resistance. This is indeed a paradoxical outcome of a diet which many pursue in order to improve their insulin sensitivity!

In the wake-sleep cycle, the ascending arousal system or “C-process” is stimulated by the secretion of CRF (corticopin releasing factor) by the hypothalamic-pituitary-adrenal (HPA) axis.  But a state of interminable wakefulness or insomnia results in cognitive deterioration. Both the “C” and “S” processes are necessary, and they must oscillate:  An unvarying simultaneous activation of both processes would not lead to cognitive stability, but rather mental deterioration.  Stress and renewal must follow one another as night follows day.

For any physiological function like digestion, muscle synthesis, or the wake-sleep cycle, the oscillation between State A and State B produces a dynamic stability that exhibits a certain dynamic range between stress and rest.   The cycle of eat-fast-eat leads to a cycling of digestive hormones such as insulin, glucagon, and adrenaline.  The cycle of wake-sleep-fast leads to a cycling between the arousal system and the sleep system.

And here is the takeway:  By exposing ourselves to alternating A and B states of increasing intensity, we build tolerance and dynamic range for the opponent processes.  We should strive to increase the magnitude of contrast between the opponent states.  I believe that we can generalize the use of dynamic capacity between allostatic states as a marker of fitness.  This can be illustrated by several examples:

Example 1.  Aerobic capacity.  Exercise phyiologists understand that athletes are able to build aerobic capacity (so-called VO2 max) by exerting themselves at or near maximal heart rate.  Their state of fitness is manifest in a reduced resting heart rate or pulse, and a higher ratio between peak VO2 and resting VO2.  This ratio or difference is sometimes referred to as VO2 reserve or VO2R, and it represents a good measure of aerobic fitness, a kind of dynamic capacity to oscillate between rest and exertion. Yet another measure of dynamic capacity is the rate at which heart rate or VO2 return to normal, after exertion

What is interesting is that training harder does not necessarily increase VO2R or dynamic capacity.  A study by the Navy Seals showed that overtraining can actually decrease VO2R, and can elevated resting heart rate by as much as 10-15 beats per minute.  Monitoring your resting heart rate is an excellent way to know if you are overtraining.  (Caveat: the heart rate measure must be used with judgement, as severe overtraining can lead to extreme exhaustion and an abnormally low heart rate).

More generally, high intensity interval training (HIIT), whether it be in the form of weight lifting, sprinting, or other metabolic training, is based on the very same premise.  Maximal exertion, into the anaerobic range, activates the full range of muscle fibers, including the ever-important fast-twitch muscle fibers, empties muscle glycogen, and activates the glycolytic pathway, resulting in an upregulation of insulin receptors (GLUT4 transporters), and improved insulin sensitivity.  But for HIIT to work effectively, it is equally important to allow adequate time for rest and recovery.  (I’ve discussed this in more detail on the Fitness page of this blog, with particular emphasis on the physiological analysis of Doug McGuff in his book, Body by Science).

For sports as varied as running and weight lifting, the well known principle of periodization recognizes the importance of variation in intensity and proper rest. In short, both high intensity training and aerobic training, if carried out with adequate rest and recovery, build dynamic range.

Example 2.  Digestive or metabolic fitness can be measured by a low basal insulin level in combination with a pattern of sharp, but brief insulin secretion in response to ingested carbohydrates or insulinogenic protein.  Low basal insulin level is seen, for example in non-industrialized populations such as the Kitavins, whose average basal insulin levels of about 4 mIU/ml are about half those of Western populations.  And yet the Kitavans consume meals with a high percentage of carbohydrates and have good insulin sensitivity.   So low basal insulin levels alone are not the whole story. The optimal pattern seems to involve an alternation between feast and fast, allowing the digestive hormones and enzymes to cycle between anabolic (insulin) and catabolic (glucagon, adrenaline, and cortisol).

This is also the premise behind the concept of intermittent fasting.  By training yourself to cut out snacks and go for longer periods of time between meals, the metabolic system — which includes not only digestive hormones and enzymes, but neurotransmitters and hypothalamic receptors — adapts to increase its dynamic capacity.  The resulting benefits are lower basal levels of anabolic hormones like insulin and catabolic hormones like glucagon and adrenaline. But just as importantly, intermittent fasting develops improved sensitivity and the ability to both ramp up and reduce these hormones quickly and responsively.

The benefits of spending time in the fasting state are numerous, including a natural detoxification and nutrient recycling process known as autophagy, and the upregulation of brain-protective growth factors such as Brain-Derived Neurotrophic Factor (BDNF).  Fasting allows for the upregulation of fat-liberating enzymes and hormones and a significant and glucose transporters, thereby improving insulin sensitivity. McEwen has compiled research showing that an appropriate level of “stress” or allostatic load will increase markers of brain plasticity. By contrast, following the conventional wisdom to eat six small meals a day of controlled glycemic foods, in the misguided attempt to “regulate” blood glucose at a constant level, deprives your body of these important restorative and protective processes.

But at the other extreme, extensive fasting or strict low carbohydrate dieting can leave the pancreas underutilized and thereby lead to a reduction in glucose transporters in the cells, since these are no longer “demanded”.  Our cells and organs tend to “economize” by synthesizing only the machinery they really need: use it or lose it.  People who abstain from or never consume milk will lose the ability to produce the enzyme lactase, so they become lactose intolerant.  Similarly, we need to regularly “exercise” our ability to secrete insulin on demand and the ability of cells to utilize glucose. This doesn’t necessarily have to occur every day, but several glucose loadings a week are probably necessary.

So the wise course is to apply “stress oscillation” to diet, and alternate judiciously between fasting and nutritious, balanced meals with a variety of macronutients and micronutrients.   Remember that the “stress” is binary: fasting represents recovery from the “stress” of eating; and eating relieves the “stress” of fasting.   A dynamic approach of hormesis involves stretching the ability to move between these two poles, increasing “allostatic capacity”.

Example 3.  Stress, health and cortisol.  Of all the hormones, cortisol has acquired a reputation as “the bad guy”.  It is well known that elevated cortisol levels are the mark of chronic stress and adrenal fatigue.  It has been suggested that higher levels of cortisol are linked to disregulated or high blood glucose levels and predispose one to diabetes. Chronically elevated cortisol also damages neurons in the hippocampus, leading to memory loss and cognitive decline. As a result, some practitioners mistakenly advise trying to minimize stress and even eat frequent meals, in order to keep cortisol at bay and avoid “stressing” the adrenal glands. But this is a one-sided perspetive.  Cortisol is necessary to normal alertness and mental function, as well as our ability to respond to sudden demands like exercise or threats. The problem comes when cortisol does not exhibit a normal morning peak level, followed by a steady decline through the day, but instead remains flat or even increases in the evening.  Chinook et al. classified four different cortisol patterns, shown below.  Pattern 1 (Graph A) is normal; Patterns 2, 3 and 4 show the flattening or later peaks that characterize dysregulation:

Diurnal or event-related elevations in cortisol are not problematic, so long as cortisol levels return to baseline at a decent rate, as in Pattern 1. According to Lovell et al., higher percieved stress levels are reflected not so much in average cortisol levels, but rather as higher basal or evening cortisol levels, and flatter diurnal fluctuations in cortisol levels. Matthews et al found that individuals with the flattest cortisol pattern (slowest rate of decline to baseline) were most at risk of coronary calcification.  Sephton et al found that flatter cortisol patterns were predictive of suppressed immunity and lower survival rates in women with metastatic breast cancer.

In short, we should be less concerned with absolute cortisol levels, than with the pattern of cortisol secretion.  As with other hormones, increased dynamic range and a robust cyclical pattern are indicative of fitness, stress-hardiness, and health.

The larger lesson.  James Loehr (about whom I wrote in my earlier post on Stress management and toughness training) has written eloquently about the use of “stress oscillation” to build athletic capicity and resilience in the corporate world in his book The Power of Full Engagement:

Balancing stress and recovery is critical not just in competitive sports, but also in managing energy in all facets of our lives. When we expend energy, we draw down our reservoir. When we recover energy, we fill it back up.  Too much energy expenditure without sufficient recovery eventually leads to burnout and breakdown…Too much recovery without sufficient stress leads to atrophy and weakness….Oscillation occurs even at the most basic levels of our being. Healthy patterns of activity and rest lie at the heart of our capacity for full engagement, maximum performance, and sustained health. Linearity, by contrast, ultimately leads to dysfunction and death. (TPOFE, pp. 29-31).

How to apply stress oscillation to your life. Let’s return to the question at the beginning of this post: How much of any kind of stress is enough, but not too much, to generate a hormetic benefit? The answer is: This is the wrong question!  You should not be striving for some magic optimum level of constant stress. Rather, you should strive to oscillate stress, by exposing yourself to intermittent, but intense sources of stress.  This builds dynamic capacity or strength. The amount and frequency of the stress are variables you can experiment with, but younow have a way to measure the benefit and know whether you are on track. The key metric is dynamic capacity. The appropriate measures of dynamic capacity depend upon what our goals are:

• For physical fitness:  a high VO2 max during exertion combined with a low resting VO2, resting pulse, and blood pressure.
• For dietary or metabolic health:  a rapid insulin and blood glucose response to food and low basal insulin and blood glucose levels
• For stress hardiness:  peak cortisol levels upon waking, followed by steady decline to low evening (basal) levels.

These may be imperfect measures, and they are subject to exceptions and interpretations based upon special health circumstances. Some of these measures are easy to implement at home; others are less convenient because they require blood or saliva analysis (which can be purchased online). But the general principle is valid:  Don’t look for average biometric values, but look for the dynamic range between high and low. And look for an oscillatory pattern that demonstrates periods of testing and building capacity, alternating with periods of rest and recovery.  I’ve discussed only three applications here in detail: digestion, exercise, and general stress tolerance.  But the principle of stress oscillation can be applied to many other applications of hormesis:  suntanning, allergen immunotherapy, cold showers or plus lens therapy.  I leave it to the curious reader to think about the physiological processes at work, and the appropriate measures of improved dynamic capacity.

The goal of hormetic stress should be to increase dynamic capacity to handle allostatic load — variable stresses — in a measureable way.  The precise level and frequency of stress exposure will vary from person to person. This is not a one-size-fits all path to health, but rather a journey that each of us must take for ourselves.  But on this journey, our engine is stress oscillation and our compass is increased dynamic capacity.

Why is it so hard to make permanent changes to your habits, your health, and your happiness?  Some of the most difficult struggles in life involve losing weight (and keeping it off), overcoming addictions, and recovering from depression. Many diets and therapies deliver great short term results, but the most common pattern appears to be relapse.  It often seems that you are destined to fulfill some biological program — that you are stuck with a high body weight set point or an addictive or depressive personality that cannot be escaped in the long run.

This pessimistic message is prevalent among those who have investigated the track records of the “helping” industries: the weight loss companies, the addiction recovery centers, and the various schools of psychology and psychiatry. Unlike the advocates, those who investigate them often find the results are less than what the practitioners might want you to believe.  In the arena of dieting and weight loss, books such as “The Dieter’s Dilemma” (Bennett and Gurin, 1982), and  ”Rethinking Thin”  (Kolata, 2008) echo the original set point theory first propounded by Gordon C. Kennedy in the 1950s; they conclude that your body weight is largely predetermined by a biological set point that is handed to you at birth, plus or minus about ten pounds. I do agree that sustained weight loss cannot be achieved through sheer will power alone, or simply by using diet and exercise in order to create a calorie deficit. Yet, while there is some plausibility to the set point theory, I am convinced that it is wrong because it overlooks some important factors. I’ve already given some of my reasons for my disagreement with set point theory in other posts on this blog (Flavor control diets, How to break through a plateau). But in this post I’ll present some strong evidence for an alternative theory, based on the homeostatic regulation of cellular receptors for hormones and neurotransmitters. This is a variable set point theory which I call the receptor control theory. This theory proposes a mechanism that controls appetite and body weight, as well as regulating the balance of  energy and pleasure in your life. It provides practical tools to lose weight and keep it off, overcome addictions without relapse, and move out of depression into happiness.

But first, let’s consider some common approaches for dealing with three different  health issues:

1. Obesity/Diabetes. To lose weight, reducing diets are employed that create an energy deficit.  The most effective of these diets work by actively modulating the levels hormones such as insulin or leptin, by modifying the type of food we eat (low glycemic or low carbohydrate are best), or the size and timing of meals.  In the case of advanced diabetes (an insulin deficiency), exogenous insulin is administered periodically in a controlled manner. Alternately, diet pills or other appetite suppressants are used to moderate certain hormones and peptides involved in satiety.  The back-up strategy is to learn how to cope with always being somewhat hungry.
2. Addiction. Addictive cravings from cocaine, alcohol, or other substances or activities have been associated with overstimulated dopamine “reward” circuits.  Some  treatments involve the use of antidepressants to elevate baseline dopamine levels, The back-up strategy is to counsel abstinence to avoid triggering the dopamine circuits in the first place.
3. Depression. To counteract depression, antidepressant drugs (typically SSRIs) are prescribed to boost levels of neurotransmitters such as serotonin or dopamine. Or, we may try non-drug supplements or dietary options to increase the level of these neurotransmitters: for example, serotonin precursors such 5-HTP,  tryptophan-rich food such as turkey and carbohydrates such as potatoes, which allow dietary tryptophan to readily produce serotonin in the brain. The back-up strategy is psychotherapy to provide insight or coping skills to better deal with the underlying depression.

The organic imbalance model. These three seemingly different treatments share a common thread: they are all based on conceiving health problems as intrinsic organic imbalances in our metabolism or neurochemistry that you are either born with or develop early in life, and over which you have little control.   Once you accept this model, there are two basic strategies: an “active” strategy to rebalance internal biochemistry, usually by means of drugs, supplements, or diet. And a “passive” back-up strategy of accepting that you are biochemically different, and counseling ways to cope with these organic conditions as best youe can, while trying to minimize the risk of triggering flare-ups due to relapse, bingeing, or depressive episodes.

Signaling compounds. I’ll focus here more on the “active” interventions which involve trying to directly rebalance the levels of “biochemical messengers” or signaling compounds circulating in our bodies. I’m referring to hormones like insulin and leptin, glucagon, or adrenaline; or neurotransmitters like serotonin or dopamine, which are produced in response to external stimuli.  According to the imbalance model, the levels of these signaling compounds are out of balance: there is a surplus or deficiency of “communication” that needs to be adjusted. The resulting “message” conveyed by the signaling compound is “too loud” or “too soft” for normal bodily function.  So to correct this, a therapeutic intervention is devised which attempts to restore our health by adjusting the amount of the signalling compound in our system.  In effect, the treatment attempts to turn up or turn down the “volume” of the message by adjusting the amount of signaling compound, in order to re-normalize our response to external stimuli.

These active medical or dietary interventions should work, if the imbalance model is correct.  But in many cases the treatments backfire:  after perhaps seeing a short term benefit the effect dissipates, and in some cases symptoms actually worsen, or side effects develop.  After some initial weight loss, the weight is regained.  Attempts to overcome addiction frequently end with relapse and failure. And depression returns. The problem is that we are not mechanical machines, we’re adaptive organisms, regulated by homeostasis. Trying to control message intensity may work for a short time, but the body outsmarts us and compensates for the intervention. Our wonderful, adaptive bodies react to the increased level of signaling compounds by becoming less responsive to them, just as we learn to tune out a dog that constantly barks for attention.  When the message volume is turned up, the receiver volume is turned down.

Our efforts to change seem to be hampered by biological programs that resist these efforts at biochemical rebalancing. Some will explain this by arguing that’s because we are born with a biological set point that our body will “defend” or an addictive or depressive personality that we can’t shake.  Try as we might to fight this in the short term, it’s almost impossible to succeed in the long run.  A lucky few may prevail, but the vast majority are doomed to their biology destiny.

Even if you manage to normalize the level of signaling compounds, you are now stuck with another problem:  you are dependent on some drug, supplement, or special dietary restriction for the long term — maybe even for the rest of your life. Drug companies and dietary supplement suppliers are happy to provide you with a lifetime supply of these compounds for a price.  I don’t know about you, but I’d rather not be dependent long term on drugs or supplements, or even restrictive diets, if it doesn’t have to be that way.

There are grounds for pessimism here.  But there may be a better solution that gives us back control of our fate:  Receptor regulation.

Receptor regulation. Receptors are “message receivers” located throughout our bodies. They are typically transmembrane proteins located on the surfaces of cells, and they bind with hormones and neurotransmitters to “receive” the signal and initiate a sequence of changes in our bodies — often profound system-wide changes in energy utilization, tissue growth, or the perception of pleasure and pain. For some reason, receptors don’t get the public attention that gets showered on the communication chemicals — the hormones and neurotransmitters.  And yet, as I shall argue, the receptors may be far more important than the signaling compounds that they interact with, because they do not change by the minute or hour, but are long-lasting parts of the control systems of our bodies.  If hormones and neurotransmitters are the “software”, receptors are the “hardware”.

The key process to understand is called receptor regulation, the process which controls the number, location and sensitivity of receptors. There are two forms: upregulation (an increase in the number and/or sensitivity of receptors in each cell) and downregulation (the reverse process). Wikipedia explains downregulation by describing how insulin resistance develops in response to elevated insulin levels:

The process of downregulation occurs when there are elevated levels of the hormone insulin in the blood. When insulin binds to its receptors on the surface of a cell, the hormone receptor complex undergoes endocytosis and is subsequently attacked by intracellular lysosomal enzymes. The internalization of the insulin molecules provides a pathway for degradation of the hormone as well as for regulation of the number of sites that are available for binding on the cell’s surface without doubts. At high plasma concentrations, the number of surface receptors for insulin is gradually reduced by the accelerated rate of receptor internalization and degradation brought about by increased hormonal binding. The rate of synthesis of new receptors within the endoplasmic reticulum and their insertion in the plasma membrane do not keep pace with their rate of destruction. Over time, this self-induced loss of target cell receptors for insulin reduces the target cell’s sensitivity to the elevated hormone concentration. The process of decreasing the number of receptor sites is virtually the same for all hormones; it varies only in the receptor hormone complex. (Italics added by me for emphasis).

So not only are the insulin receptors drawn inside the cell (like a turtle into its shell); they are also actively digested and degraded, making them less available to readily redeploy when glucose and insulin levels drop again.  New receptors are always being synthesized, but they are degraded more quickly than they can be replenished if insulin levels remain high. The resulting downregulation of insulin receptors forms the basis for the condition of insulin resistance, in which insulin at normal levels loses its ability to efficiently shuttle glucose from the bloodstream into liver, muscle, brain, adipose or other tissues; the body responds by further increasing insulin, resulting in a vicious cycle of hyperinsulinemia. Reversing this process — growing new insulin receptors — takes time and requires sustained periods with low circulating levels of insulin in order to foster the growth of new receptors.

It is quite revealing to look at how how receptor regulation can undermine “message control” treatments,  due to the way the body adapts. Let’s take a look again at how this plays out in the above three examples of obesity, addiction, and depression:

1.  Obesity. Obesity is associated with high levels of two hormones: insulin and leptin. Normally, an increase in the level of either of these two hormones induces satiety upon reaching the hypothalamus in the brain. Leptin levels in the body increase with the amount of body fat, so leptin has been proposed as a physiological correlate for our “set point” weight: when body fat falls below a certain level, appetite induces us to eat more; when body fat increases, the associated rise in leptin levels leads to satiety. Insulin plays a similar but different role; it tends to regulate appetite on a shorter timescale than leptin, varying during each meal, and is more closely associated with visceral fat of the type more commonly found in men, whereas appetite regulation by leptin operates on more of a daily timescale and responds more closely to subcutaneous fat of the type more common in women. Insulin, of course, is directly involved with the storage and release of metabolic fuels. There are also many other regulatory hormones and sensory peptides, such as ghrelin, CCK and PYY, which adjust appetite based upon meal timing, gut sensations, and other inputs.  But insulin and leptin are key drivers of appetite.

The discovery of leptin, the “satiety hormone” by Jeff Friedman at Rockefeller University in 1993 provoked great excitement and expectations.  A well written account of this discovery is detailed in “Rethinking Thin“, the above-mentioned book by Gina Kolata. Studies in leptin-deficient ob mice and humans showed that individuals with defective production of leptin became ravenous and obese.  So the logical conclusion was leptin itself may be the magical “set point” compound that determines our weight.  Therefore, we should be able to provide leptin to the overweight to help them shed pounds. And in fact, adminstering leptin does work to counteract obesity in mice and humans that are genetically incapable of producing normal leptin, as Kolata describes poignantly in her chapter “The Girl Who Had No Leptin”.  It even works initially in normal or lean mice to reduce body fat. Amgen acquired the rights to leptin from Rockefeller University for $20 million plus royalties in anticipation of imminent commercialization. But after a long-term study in humans, the October 1999 issue of  JAMA reported disappointing results indicating very little weight loss, and even that in only in a small percentage of subjects. As Kolata observes:

The question, though, was, Why didn’t the obese people in Amgen’s study respond to leptin? The possibiity, or perhaps the likelihood, was that leptin was not their problem. These people were making plenty of leptin–they were not the human equivalent of the ob mice. And since adding more leptin did not make them lose weight, it must be that the hormone was being blocked from acting somewhere along its passage from the fat cells to the appetite-controlling pathways in the brain…Then [scientists] discovered that leptin can do something else. It can actually change the brain’s wiring diagram, strengthening circuits that inhibit eating and weakening the ones that spur the appetite. It can exert this effect at a critical period early in life, perhaps influencing appetite and obesity in adults.  And, in adulthood, leptin can again alter the brain’s wiring, permanently changing an animal’s appetite and weight. (RT, pp. 163-165).

The problem is often that excessive sustained levels of leptin, common in the overweight or obese,  can cause “leptin resistance” in which the leptin receptors are downregulated, so that they are fewer in number and become less sensitive to the leptin signal. As Byron Richards indicates in The Leptin Diet:

In overweight people, the communications involving insulin and leptin are inefficient. It is like making a phone call where no one answers. Insulin resistance and leptin resistance mean that the hormones don’t communicate efficiently in response to food. Thus a person has to overeat in order to get enough leptin into the brain to get a full signal. The pancreas may not hear the leptin signal to stop making insulin, which leads to excess insulin, fatigue, and possibly even more hunger within a few hours of eating…Several hours following the meal the extra insulin ends up taking too much sugar out of the blood, making a person hungry and tired-headed. (TLD, p 36)

With leptin resistance, adding more leptin no longer effectively inhibits appetite, because the brain and body have a reduced ability to respond to the extra leptin.  Conversely, lean individuals typically have more leptin receptors and greater leptin sensitivity, so their appetite is satisfied even at reduced leptin levels.  In short, the leptin system adapts so that the number of leptin receptors adjusts to the amount of leptin.

Interestingly, obesity is also associated with reduced number of receptors for dopamine, a neurotransmitter associated with pleasure or reward circuits in the brain. In 2001, Gene Jack Wang and Nora Volkow of the U.S. Department of Energy’s Brookhaven National Laboratory used Positron Emission Tomography (PET) brain scans to look at dopamine receptors in the brains of obese and normal individuals:

Obese individuals, the scientists found, had fewer dopamine receptors than normal-weight subjects. And within this obese group, the number of dopamine receptors decreased as the subjects’ body mass index, an indicator of obesity, increased.  That is, the more obese the individual, the lower the number of receptors.

A 2008 study of women and adolescent girls in New Zealand showed that this receptor deficit is at least partly genetic. The overweight females had the Taq1A1 gene that is associated with fewer dopamine receptors. This receptor deficit in the obese led them to overeat to achieve the level of pleasure or satiety that normal individuals reached with less food. This reduced level of dopamine receptors tends to make life a bit less pleasant for the obese when they are hungry and without food. Ingestion of food, particularly carbohydrates, temporarily raises the level of dopamine, eliminating the “pleasure deficit” and rewarding eating behavior.  Excessive eating or bingeing raises the dopamine levels even higher than normal, which can lead to a further downregulation of dopamine receptors, only worsening the craving problem. This effect is not only influenced by genes, but by diet; a 2010 study of rats fed a supermarket “junk food” diet showed raid desensitization of dopamine receptors a significant increase in appetite, and an unwillingness to return to eating “healthy” food.

The connection between obesity and the number and sensitivity of dopamine receptors is perhaps not so surprising, given how highly rewarding food can be for the obese; for many of the overweight, food becomes an addiction.  It is still quite striking that this translates to such a significant decline in the number of dopamine receptors, while the baseline level of dopamine actually increases.  Here, as with insulin and leptin, we have yet another example of reduced receptor levels being associated with obesity.  By analogy with insulin resistance and leptin resistance, we might say that the strong appetite of the obese is a direct result of “dopamine resistance”.

2. Addiction. What is particularly interesting is that these low levels of dopamine receptors are also characteristic of drug addicts and alcoholics.  Nora Volkow, one of the directors of the Brookhaven study, subsequently became director of NIDA, the National Institute of Drug Abuse. part of NIH, but her research on addiction actually predates the study she did on brain activity in the obese. She used PET brain scans to study dopamine receptors levels in alcoholics, cocaine addicts, and addicted smokers.  And, as you might guess, the same pattern of reduced levels of dopamine receptors was observed in addicts vs. non-addicted controls.  This is illustrated in the PET scan to the right, which shows dopamine binding activity for addicts (top row) vs. non-addicts (bottom row). Regions of greatest dopamine receptor activity are indicated with a color scale starting from red (most active), descending through yellow and green to blue and purple (least active).

The mechanism downregulation of dopamine receptors by cocaine has been elucidated:

Cocaine binds tightly at the dopamine transporter forming a complex that blocks the transporter’s function. The dopamine transporter can no longer perform its reuptake function, and thus dopamine accumulates in the synaptic cleft. This results in an enhanced and prolonged postsynaptic effect of dopaminergic signaling at dopamine receptors on the receiving neuron. Prolonged exposure to cocaine, as occurs with habitual use, leads to homeostatic dysregulation of normal (i.e. without cocaine) dopaminergic signaling via down-regulation of dopamine receptors and enhanced signal transduction. The decreased dopaminergic signaling after chronic cocaine use may contribute to depressive mood disorders and sensitize this important brain reward circuit to the reinforcing effects of cocaine (e.g. enhanced dopaminergic signalling only when cocaine is self-administered). This sensitization contributes to the intractable nature of addiction and relapse.

3.  Depression. A reduced number or sensitivity of neurotransmitter receptors has also been linked to mood disorders such as major depression. Depression has been associated with shortages of at least two neurotransmitters:  dopamine (which is associated with drive, motivation and pleasure), and serotinin (which is associated with a sense of well-being and pleasure).  While dopamine receptors are located largely in the brain, a little known fact is that only about 20% of serotonin receptors are in the brain, most of the other 80% are in the gut, blood platelets, and other organs.  That might help explain why serotonin is also associated with food and satiety.   Different types or depression are often associated with a different imbalance of neurotransmitters, so despite the prevalence of SSRIs, which are intended to restore serotonin levels, some forms of depression respond better to antidepressants which boost dopamine levels.

While antidepressants work for many people, a surprising number — some estimates put it at 50% or higher — are unresponsive. Furthermore, long term use of SSRI’s can have the effect of downregulating serotonin (5-HT2A) receptors with adverse results:

Another adaptive process provoked by SSRIs is the downregulation of postsynaptic serotonin 5-HT2A receptors. After the use of an SSRI, since there is more serotonin available, the response is to decrease the number of postsynaptic receptors over time and in the long run, this modifies the serotonin/receptor ratio. This downregulation of 5-HT2A occurs when the antidepressant effects of SSRIs become apparent. Also, deceased suicidal and otherwise depressed patients have had more [presynaptic] 5-HT2A receptors than normal patients. These considerations suggest that 5-HT2A overactivity is involved in the pathogenesis of depression

The last sentence in the above quote again points to the fact that a deficiency of post-synaptic serotonin receptors, in combination with  an excess of serotonin from diet, antidepressants, or elsewhere,  may play a role in both the genesis and worsening of depression.  The same phenomenon of receptor downregulation together with excess neurotransmitter has been noted with other antidepressants, such as MAO inhibitors and buproprion, that stimulate the production or prolong the lifetime of dopamine in the synapse.  This can lead to tolerance and withdrawal effects.

In short, in all these cases — obesity, addiction, and depression — receptors are becoming less sensitive to a signaling compound as a reaction to excessive levels of that compound.  So too much insulin and leptin lead to insulin and leptin resistance, too much dopamine to a downregulation of dopamine receptors.

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HOW TO UPREGULATE YOUR RECEPTORS. So if directly changing the amount of signaling compounds is frequently frustrated by receptor downregulation, is there anything you can do to upregulate the receptors?  Fortunately, the answer is yes.  There are a number of measures that have proven particularly effective for deliberately increasing the number and sensitivity of key classes of receptors:

Step 1:  Strenuous exercise. Regular, intense exercise can upregulate your insulin receptors. In Dr. Bernstein’s Diet Solution, Richard Bernstein explains the role of exercise in actually reversing insulin resistance by growing new muscle tissue, and by increasing the density of glucose transporter receptors in muscle and other tissues.  While his advice is directed primarily towards diabetics, it applies more broadly to anyone with some degree of insulin resistance That includes most of us.  According to Dr. Bernstein:

The higher your ratio of abdominal fat to muscle mass, the more insulin-resistant you’re likely to be. As you increase your muscle mass, your insulin needs will be reduced…Long-term, regular strenuous exercise also reduces insulin resistance independently of its effect upon muscle mass…In my experience, it takes about two weeks of daily strenuous exercise to bring about a steady, increased level of insulin sensitivity…via increased production of glucose transporters in muscle cells. (DBDS, p. 170-1).

Furthermore, the exercise must be strenuous and “anaerobic” – not aerobic.  There are two reasons for this:

First, the blood sugar drop during and after continuous anaerobic exercise will be much greater than after a similar period of aerobic exercise. Second, to accomplish efficient transport of glucose into muscle cells, as muscle strength and bulk develop, glucose transporters in these cells will greatly increase in number. Glucose transporters also become more numerous in tissues other than muscle, including the liver.  (DBDS, p. 180)

Glucose transporter (GLUT4) receptors are upregulated by intense exercise.  A study reported in the New England Journal of Medicine showed that this upregulation begins to happen within hours, but significant and sustained improvement requires repeated exercise sessions over several weeks.  When insulin levels are kept low, the glucose transporters migrate from a location inside the cell to protrude beyond the cell surface, becoming more available to bind glucose and shepherd it into the interior of the cell.  With time, the cells can actally express or “grow” additional receptors, increasing the overall rate of glucose transport.  This increased response rate is synonymous with “insulin sensitivity”.

The benefits of anerobic exercise extend not only to upgregulation of insulin receptors, but also to maintaining high levels of dopamine “reward” receptors. A study of exercised rates by McRae et al at University of Texas showed that regular exercise has a protective effect on D2 dopamine receptors, while keeping levels of dopamine (DA) and dopamine metabolite (DOPAC) low.  Unexercised rats saw both a decrease in D2 receptor density and an increase in circulating dopamine.

Step 2:  Calorie restriction and intermittent fasting. Another brain scan study at Brookhaven National Laboratory showed that restricted eating led to higher numbers of dopamine receptors in obese rats:

The scientists found that genetically obese rats had lower levels of dopamine D2 receptors than lean rats. They also demonstrated that restricting food intake can significantly increase the number of D2 receptors, partially attenuating a normal decline associated with aging.

This research corroborates brain-imaging studies conducted at Brookhaven that found decreased levels of dopamine D2 receptors in obese people compared with normal-weight people,” said Brookhaven neuroscientist Panayotis (Peter) Thanos, lead author of the current study, which will be published online in the journal Synapse on Thursday, October 25, 2007.

One of the essential points to understand here is that if calorie restriction and intermittent fasting are effective, it is not for the reason that most people think explains this (that you are creating a calorie deficit).  Rather, intense exercise and fasting work because they resensitize and grow your insulin and dopamine receptors in a way that allows you to get enough energy and pleasure from eating less food.   This means that not only are the receptors upregulated, but you also get the energy and pleasure when you need it.  So restricting calories is not good enough.  You must eat foods that maximize insulin senstivity (e.g. containing adequate essential fatty acids, protein, magnesium, etc.) and foods which give you enough pleasure so as to satisfy your “pleasure budget”, but not so much as to downregulate your dopamine receptors.  My experience is that intermittent fasting, using a varied diet, is the best way to do this.  One reason that pure “starvation diets” like that used in the Minnesota Starvation Experiment may have failed is that the diet failed to supply adequate nutrients that to support receptor function for cellular energy and pleasure.  (The 1560 calorie/day regimen consisted only of potatoes,  rutabagas,  turnips,  bread and macaroni — so go figure!)

A particularly effective protocol for improving insulin sensitivity and upregulating glucose transporter receptors is called “fasted workouts”: a combination of intense exercise and intermittent fasting, in which eating is postponed until after one works out.  One of the foremost practioners of this approach is Martin Berkhan, who I’ve referenced on the Fitness page of this blog, and whose Leangains blog I’ve listed under the Diet links.  Martin summarizes the research by DeBock et al. and Cluberton et al. that documents the physiological beneifts of fasted workouts, including enhanced insulin sensitivity based upon a six-week study with four 60-90 minute workouts per week. The study controlled for dietary intake, and compared results of those who fasted (F) with the control group (C) that ate prior to working out. Among other variables, the study compared changes in the levels of the GLUT4 transporter, a type of insulin receptor in the muscles, between the F and C groups:

Glucose transporter type 4 is a protein responsible for insulin-regulated glucose transport into the muscle cell. It increased by a whopping 28% in F but only 2-3% in C (not mentioned in the paper but this is my estimate based on the graphs). This partly explains why F saw superior results in regards to glucose tolerance and insulin sensitivity. Since GLUT4 is triggered by AMPK, which is increased when glucose availability is low, i.e. during fasted training, one would assume the GLUT4 increase could then be explained by an increase in AMPK. This was found to be true: AMPK increased by 25% in F, which correlated closely with the increase in GLUT4 content.

Step 3: Deconditioning and extinction. Pleasure reward circuits do not change overnight.  But the good news is that there is plenty of evidence that these reward circuits can be extinguished by classical conditioning techniques.  I’ve discussed these deconditioning techniques in depth on the Psychology and Diet pages of this blog, and I’d recommend looking there for details.  Extinction involves merely refraining from the undesired behavior (eating, addictive drugs) and allowing the cravings to happen without reinforcing them.  It may surprise you how quickly your reward circuits recover, and it is very likely that this involves upregulation of dopamine receptors, so that the brain is more easily “satisifed” without the previously craved behavior. Deconditioning is more active than extinction; it requires actively exposing yourself to cues which normally set off the addictive response.  This may sound extremely difficult, but is attested to by extensive research, as well as the personal experience of several people who have posted here on the Forum, including myself.   One of the more successful appliations of active deconditioning is the Sinclair Method, which has been used successfully to extinguish alcoholism while training the former alcoholic to drink moderately. The key is the use of a dopamine blocker, naltrexone, to block the reward circuits during exposure.

Any type of extinction should benefit from simultaneous reinforcement of healthy alternative sources of pleasure, while engaging in exercise and intermittent fasting to rebuild the density and sensitivity of receptors.  Unless you increase your level of dopamine receptors, you’ll always be vulnerable to the temptation of any pleasure that can “fill your pleasure deficit”.

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THE RECEPTOR CONTROL THEORY. Based upon a synthesis of extensive evidence, I’m putting forward in this post an alternative to the classic set point theory of Gordon Kennedy:  the receptor control theory.  This is a general hypothesis of biological regulation which applies to more than just weight control; it applies to any homeostatic variable that is controlled by cellular receptors — even, for example, pleasure and motivation. Whereas the classic set point theory of body weight posits a fixed genetic set point for each individual,

the receptor control theory postulates that our set points for regulating weight, energy, or pleasure are variable; they are directly related to the number, sensitivity and location of cellular receptors in our bodies, and can be modified by changing the number and sensitivity of these receptors.

For example, the set point for your body fat is controlled by insulin and leptin sensitivity, which is determined by the number and functional sensitivity of insulin and leptin receptors throughout your body.  As the number and sensitivity of insulin and leptin receptors decreases, body weight set point goes up. But unlike the set point theory, body fat set point can also go down by increasing the number and sensitivity of these receptors — for example by the use of strenuous exercise, intermittent fasting, and extinction.

If you don’t change the number and sensitivity of your receptors, your set point will not change.  Under these circumstances, the receptor control theory agrees with the classic fixed set point theory. However, the receptor control theory provides a way to change your set point by upregulating your receptors.

The pleasure budget. The receptor control theory goes beyond weight management to explain more generally the regulation of pleasure in your life.  If you have ample dopamine receptors, then a wide variety of stimuli– including food, social interactions, work, and other interests– should provide you with sufficient pleasure to make life not just bearable, but interesting.  However, if you end up with an undersupply of dopamine receptors — whether it be from birth, addictions or unremitting stress — then your baseline pleasure “set point” will be low and you’ll be vulnerable to depression, low self-esteem and other aspects of unhappiness. Addictive escapes may provide temporary (but unsustainable) bursts of dopamine, serotonin, and other feel-good neurotransmitters, but at the cost of further downregulating dopamine receptors and feeling worse later on.

It may be the case that all of us have a certain “pleasure budget” — perhaps we need a certain amount of pleasure every week, and we’ll find a way to get it, one way or another.  One of the commenters (zdd) to my earlier post on The opponent-process theory of emotion expressed this point well, when speculating about why diets like Shangri-La and Atkins work so well initially, but eventually become less effective:

If there is a set point, I believe it’s not a weight set point but rather a pleasure set point. When you don’t reach the set point, cravings start and when you go over the set point (staying too long at the fair) you get feelings of aversion.

I doubt if the pleasure set point changes very much. People simply switch sources of pleasure. Stop smoking, and you start eating more. Much of the pleasure of being on this diet comes from the pleasure of feeling in control. Once the novelty of control wears off people will have to look for other sources of pleasure or they will go back to getting pleasure from food.

I think this insightful comments carries a useful warning: that behavioral changes such as diets which cut off one source of pleasure may require us to find a way to replace that source of pleasure, or else risk rebounding from the diet and regaining the weight we lost.

The good news here is that there are proven ways to raise our “pleasure” set point.  The bad news is that they require significant and sustained effort – no quick fixes.  And yet it is the most sustainable way to increase pleasure in life.  To paraphrase a saying about fishing sometimes attributed to the Bible: “Give someone a neurotransmitter and they’ll feel good for an hour; teach someone to grow more receptors and they’ll feel good all the time.”

Explanations. The receptor control theory explains a number of observations that cannot be accounted for by classical set point theory:

1. Biology is not destiny. Individuals do differ genetically in their tendency to gain weight or to be prone to addiction or depression.  You are born with a certain density of receptors and this can be influenced further during prenatal and postnatal development.  But it is not the end of the story. The types of foods you eat and the frequency of eating have strong effects on insulin and leptin sensitivity.  Likewise, exercise, hard work and a stoic practices can sensitize your dopamine receptors and make you happier and less prone to depression.
2. Obesity is not a constant. Both the weight gain of individuals as they age, and the obesity epidemic of recent decades are often blamed on “calorie imbalance”: eating too much and exercising too little. But this doesn’t explain why this caloric imbalance is happening now as opposed to earlier. Sometimes the uptick in obesity is blamed on the increasing availability of tasty high-calorie food and a less active lifestyle. But that explanation cannot be right, because there has always been tasty food. And as Kolata has shown, controlled interventions to reduce calories and enforce more activity have a poor track record.  The reason that body weight set points are rising has more to do with changes in the amounts of food and exercise, as it does with specific types of food, eating patterns and exercise–and the long term hormonal influences of these changes on receptor sensitivity.
3. Permanent weight loss is still possible. Granted, most diets don’t work. Quick weight loss diets don’t work because they don’t allow a biologically realistic amount of time for receptors to upregulate; receptor upregulation is a gradual process that requires persistence and effort. Certain diets are quite effective in the short term, including low carbohydrate diets, low glycemic diets, and the Shangri-La Diet (which temporarily suppresses appetite). These diets will temporarily change levels of hormones, neurotransmitters and other signalling compounds to induce satiety and weight loss. However, unless appetite circuits are permanently “re-wired” by upregulating hormonal and neural receptors, weight loss will be temporary.  Appetite will remain vulnerable to coming back like a tiger, and you may return to your old set point weight — perhaps even plus a few pounds.  The best way to upregulate metabolic and appetite receptors is by strenuous exercise, intermittent fasting or deconditioning.  Given enough time, persistent and habitual dietary changes can lead to permanent weight loss, particularly when combined with reduced eating frequency, intense exercise, and deconditioning.

Biological basis for Hormetism. The receptor control theory also provides us with a some biological underpinnings for Hormetism and Stoicism, as advocated in this blog. Hard work –tough, uncomfortable and challenging activities–can lower our metabolic and pleasure set points, helping us to lose weight and making us less vulnerable to addictions, cravings and depression.  What is exciting to me is that this theory may provide a possible biological basis for the psychological Opponent-Process Theory of Richard Solomon.  The basis is located not in transient chemical messengers like neurotransmitter and hormones, but rather in the adpatable receptors located throughout our body on every cell.  These receptors are part of the hardware or firmware of our bodies and brains.   Receptors are a part of us that cannot be changed overnight, but can only be changed with persistent effort.  (And they will not disappear so readily either).

I will be the first to acknowledge that at this point the receptor control theory is just that — a theory.  It has support by scientific evidence, but many questions remain.  And yet it is a productive theory which generates many testable hypotheses.  It provides us with a possible basis for understanding the benefits of less-studied hormetic or Stoic practices such as showering or swimming in cold water, radiation hormesis, or allergen immunotherapy.  Do these types of stress also result in upregulation or downregulation of specific cellular receptors involved in pain perception, cellular repair, inflammation or immune response? Can we measure and better understand these responses at the level of receptors? Are there practical ways to measure the number and sensitivity of our receptors, so that we can track progress? Receptor change is probably only one of many mechanisms that explain hormesis, but it may be an important and underappreciated one.  These questions make good topics for future posts.

Finally, unlike the classic set point theory, the receptor control theory is not fatalistic, but is optimistic:  By combining insights as old as ancient Stoic philosophy with a contemporary scientific understanding of psychological conditioning and the plasticity of cellular signal receptors and receptor circuits, we can work to achieve fitness and weight loss, freedom from addictive compulsions, and chart other major changes in our metabolic and psychological well being.

And then…progress stalls. You’re still eating the same foods, faithfully completing your workouts, but your weight loss stalls, perhaps the scale even goes up a few pounds. The progress you make at the gym similarly maxes out…you can’t lift any more weight, your running speed or distance maxes out…maybe even some soreness or injury sets you back a bit. You’ve hit the dreaded plateau.  Sometimes it lasts a few weeks and progress resumes. But it can last months. And it saps your morale because you are not getting any more return on your invested effort. In all likelihood, you give up or cut back, your discipline withers. Your weight goes back up, maybe adding a few pounds on top of where you started, and you cut back on or cut out your exercise program. The genie is back in the bottle.

What causes plateaus?  Are they inevitable endpoints in any effort to make progress? Or are they at best temporary way-posts or resting points that you can move beyond with the right approach?  The school of thought that says that plateaus are unavoidable indicators of biological limits is called the Set Point theory. I think that the Set Point theory is wrong, and that there is a reliable way to push past plateaus to bring about substantial weight loss and improved fitness.

Conventional plateau busting suggestions. Before we get into the Set Point theory, let’s take a look some typical suggestions you’ll get if you google “plateau busting” or “break through plateau”:

To break through exercise plateaus:

1. Increase exercise intensity
2. Take a break – don’t overtrain
3. Try new exercises
4. Mix up your routine, change the order of exercises
5. Wait out the plateau

To break through diet plateaus:

1. Eat more frequently, don’t skip meals
2. Eat different foods
3. Drink more water
4. Wait it out

Many of these are good suggestions, and they can work to jump start progress. But I suspect that more often than not, these approaches at best result in temporary progress, lasting perhaps a few days or weeks. Progress is soon reversed and you are right back on the original plateau. Eating more frequent small meals might lead to a temporary boost in metabolism and better blood glucose control, but it is unlikely to result in any permanent weight loss, once the body adapts. The least effective of the above suggestions is to wait it out. If you don’t change the input, you can’t expect the output to change. So while these recommendations might help get you started, they are unlikely to lead to permanent, long term change.  But where does that leave us?  Are we doomed to stay on the plateau forever?

The ‘Set Point’ theory. I discussed the Set Point theory in a previous post on the Shangri-La Diet, just one of many diets based upon the set point theory. (See:  Flavor Control Diets). Set point theories trace back to the lipostatic (“constant fat”) weight control theory of Gordon C. Kennedy, based upon research he did on rats in the 1950s. Kennedy found that when he varied the caloric density of rat chow, his rats initially gained or lost weight, but they eventually adjusted how much food they ate, or their physical activity levels, so as to re-establish their original weight. Kennedy took this to be evidence that rats have an internal set point, a “natural weight” which their physiology acts to maintain against external changes to environment. The set point concept was later extended to explain the persistence of stable weights in human, in the face of variation in dietary intake and energy expenditure. The physiological explanation is that your metabolism slows when you attempt to diet and your weight drops below its set point; this also typically makes you less inclined to be active.  Conversely, overeating leads to a ramped up metabolism, which puts the brakes on weight gain; it also often gives you the extra energy to be active and burn off calories.  In the end, try as you might, you just can’t budge your set point weight.

The set point theory is ultimately a rather pessimistic view. (For a typical popular portrayal of the theory, take a look at this discussion of set point theory in the context of eating disorders). The underlying assumption is that each of us is born with a natural weight (or more accurately, a weight “program” that specifies a weight set point that changes as a function of age).  We can temporarily deviate from our pre-programmed set point weight by extreme diets, intense exercise, emotional events or illness, but eventually we will return to equilibrium, to our intrinsic, biologically predestined set point weight.  We best off not to fight our set point, but to accept it. Some adherents of the Set Point theory believe that the set point can be changed, but only by means of a sustained intervention.  For example, Seth Roberts, in his Shangri-La Diet, prescribes the use of “flavorless calories” (such as oil or sugar water) to break associations between flavor and calories and trick the metabolism into lowering set point.  Set point can also be changed by other interventions such as diet pills or special appetite suppressing foods.  However, once the dietary or medical intervention is stopped, the set point will return to its “natural” level, and the weight will creep back on.  Permanent, lasting change is impossible without the intervention, according to this Set Point theory, since progress requires lifelong dependence on some external crutch, some substance which hopefully is healthful, but nevertheless which we can never afford to go without for very long.

If you think about it and look around, it soon becomes clear that the Set Point theory can’t be right, or at least it is too simple, because it can’t explain certain undeniable facts.  Despite the numerous people who have failed to keep the weight off, we all know people who have lost huge amounts of weight — and kept it off. One of the most remarkable stories is that of Jon Gabriel, who dropped from 400 pounds to a very muscular 189 pounds and published his story and his insights in a best-seller called The Gabriel Method. Many people have replicated Gabriel’s type of “non-dieting” weight loss, to varying degrees.  We also know that various ethnic populations, such as Pacific Islanders and the Pima, who are healthy and trim on their native foods and in their native environment, frequently become morbidly obese and diabetic when they transition to a Western diet and lifestyle. And the American population as a whole is experiencing skyrocketing rates of obesity since the 1970s, which cannot be explained in terms of genetic programs. So the experience of both individuals and populations testifies against the Set Point theory.

And yet, there is at least some plausibility to the Set Point theory, or it would never have taken hold so strongly.  There are undoubtedly periods in our lives where our weight is remarkably stable, and where we experience resistance at our efforts to lose weight or get fit. Even outside of weight control and fitness, whenever we try to change ingrained habitual behaviors, there is a strong tendency to return to where we started.  In both physiological and psychological terms this is called “homeostasis” — the strong tendency of an organism to resist change. Homeostasis is generally beneficial because it helps us to maintain a healthy stability in the face of environmental changes that could be potentially detrimental or even lethal, if not resisted.  But at the same time, homeostasis can sometimes be the enemy of positive changes, such as losing excess weight, or becoming more fit.

If the Set Point theory is based upon a recognition of homeostasis, a well established biological reality, what could possibly be wrong with it?  Well, upon looking more closely, it turns out that the Set Point theory is based upon a serious misunderstanding of homeostasis.

What homeostasis really is and how it really works.  The big mistake in the Set Point theory is that it fails to realize that homeostasis applies only to our internal environment, not to our external physical condition. The organism does not inherently defend any particular macroscopic bodily features such as total fat or muscle mass, or external fitness. What the organism defends is the internal environment, the so-called “milieu interieur“, as Claude Bernard called it in the nineteenth century. Homeostasis appropriately applies to certain essential internal physiological variables, at the level of the cell or the bloodstream:  pH, the concentration of glucose (or more accurately, glucose+fatty acids+ ketones), electrolytes, and certain other essential physiological metabolites. These essential physiological parameters must be tightly controlled within narrow bounds — not as a constant, but as a range — in order to support cellular function. For example, blood glucose should be kept within the range of about 70-150 mg/dL; if it drifts outside of this range, hormones like insulin, glucagon or epinephrine will normally act to bring it back within range. If the body is unable to successfully regulate these key parameters, it may enter a state of shock and tissue damage, loss of consciousness, or death may ensue.

So if there is a “set point”, it applies not to body weight, fat, muscle, conditioning, or other outward characteristics; rather, it applies only to the inner environment of our cells and the bloodstream that nourishes them and supplies their energy.  Our brain and endocrine systems don’t directly detect our weight or muscularity — they sense only what is present in the immediate cellular environment.  There are certain hormones, such as leptin, which do to some extent vary as a function of body composition, but they do not do so in an absolute way, and can alter their response over time in a dynamic fashion. Body weight and fitness tend to act “as if” there is a set point only because they are influenced strongly by energy metabolism, and are linked to them in the short term. So in the short term, weight loss does tend to produce an energy deficit that is reflected by blood metabolites, cellular response, and even hunger. And in the short term, if nothing is done to change this connection, the set point theory seems to work. However, this is at best a temporary type of stability which is not centrally controlled, but rather results from a “balance of forces” that can be dynamically altered over time. Gary Taubes expressed this point well in his critique of the lipostatic set point theory:

Life is dependent on homeostatic systems that exhibit the same relative constancy as body weight, and none of them require a set point, like the temperature setting on a thermostat, to do so. Moreover, it is always possible to create a system that exhibits set-point-like behavior or a settling point, without actually having a set-point mechanism involved. The classic example is the water level in a lake, which might, to the naive, appear to be regulated from day to day or year to year, but is just the end result of a balance between the flow of water into the lake and the flow out. When Claude Bernard discussed the stability of the milieu interieur, and Walter Cannon the notion of homeostasis, it was this kind of dynamic equilibrium they had in mind, not a central thermostatlike regulator in the brain that would do the job rather than the body itself.  (Good Calories, Bad Calories, p. 428).

Once you grasp this point, it becomes obvious that you can have a stable, sustainable inner environment whether you are fat or skinny, fit or flabby.  On the other hand, the good news is that you can significantly change your body composition and fitness — and maintain the new state — so long as you can do so while maintaining internal homeostasis.  In fact, you can make major, lasting changes to your body and fitness by understanding how homeostasis works.

A stepwise evolutionary model of plateau busting. So if we are not constrained by arbitrary set points, if our body weight, fat, and muscle composition are not predetermined at birth, why is it so hard to make progress, and how can we progress to a new state? I think the best way to answer this question is to think about how systems evolve and adapt.  Adaptation is typically not a smooth, continuous process, but moves from one relatively stable state to another through a series of discrete, quantum steps.  Mathematical analysis of complex adaptive systems — such as cells, individual organisms, biological species, and human organizations and economies–shows that they typically display stable “nodes” or “attractors”– states which tend to resist change — until the change is big enough, and in the right direction, to move them to a new stable state or “orbit”.

A useful analogue for how this works comes from the Darwinian explanation of how biological species evolve.  Species are typically very stable in the short term (which can be thousands or millions of years on the timescale of evolution).  Species resist genetic change because a common breeding population exerts conservative forces that tend to keep variation within a limited range, so the population traits remain stable.  But every so often, new or divergent traits appear within sub-populations in response to environmental pressures.  If such a sub-population becomes reproductively isolated for long enough, perhaps by due to geographic separation, it can continue to grow far enough apart genetically that the new sub-population can no longer interbreed with the original breeding population.  In this way, a new differentiated species is born, with no “bridge” back to the original species.

Individual adaptation is of course not the same thing as species adaptation. But there is at least this much similarity:  if the adaptation is large enough, and if there arise new forces which act to stabilize the adaptation, then a stable change is possible.  If the stability persists long enough for the balance of forces to change, the adaptation will be “permanent”, with no easy reversion to the original state.  However, some sort of “separation”, analagous to geographic isolation, is needed to prevent reversion or “backsliding” to the original state.  Just as a river or ocean separating two islands can keep two sub-species from rejoining, there needs to be some type of “habit separation” between new and old patterns to prevent us from going back to where we started.

A good mental model for this is crossing a stream which is broken up by a series of large boulders. Getting from one side to the other may seem like an impossible task. It certainly cannot be done with a single bounding leap.  But if the task is broken down into a series of small steps, each of which is a stable “boulder”, then it can be done.  If the boulders are far apart, you may hang out for quite a while on each boulder, getting your footing and balance. But then at the right time, with enough confidence, you decide to make your move to the next boulder. Each step is still a challenge and takes some preparation, but with preparation and sufficient strength, it is within your reach.  By the time you are to the other side, it is equally hard to return to where you started. Just as biological evolution proceeds stepwise, and generally without reversion, to a new space, so can individual adaptation evolve to a new stable state through a series of intermediate “resting points”, each stable in their own right. And if these resting points are far enough apart, it will be hard to return to the original place you started.  But, applying this to “plateau evolution”,  a stream with well spaced boulders is preferable to a stream crossed by a continuous foot bridge, because the bridge makes it too easy to re-cross the river back to where you started.

How does this look in practice? The stepwise evolutionary model is not mere theory, but something I have experienced myself. And I think it may provide a more general model of how we can adapt and bust out of plateaus that appear (but only appear) to be holding us back.  The figure below shows the most recent 8 months of my weight loss.  I started out at 185 pounds several years ago and just recently reached my goal of 150 pounds.  But only since February 2010 did I keep an almost daily record of weights. I annotated my weight log with comments regarding various changes I made to my eating or habits, including both sustained and individual events:

When you look closely at the day by day weight measurement in any period of a few weeks, you tend to see only a lot of fluctuation over a range of about 4-6 pounds.  These are plateaus.  A plateau does not mean a constant weight, but rather what stock investors might call a “trading range” — a normal range of variation around some average weight.  But periodically there is a move of 3-4 pounds that seems to endure, to “take”.  And then there is a new average weight with a range of variation around it. These shifts may not become apparent immediately as permanent shifts in the average, because the magnitude of the shift (3-4 pounds in my case) can actually be smaller than the “trading range” variation around the old average (4-6 pounds in my case).  Only after several weeks have passed, does it become clear that a new “plateau” has been established, because the weight is not going back up.

What causes the shifts? The key question is how to explain the moves to the new plateaus.  From my limited analysis, I think I have an answer:

1. Single, unique events are incapable of establishing new plateaus.
2. Gradual, continuous changes are generally not likely to lead to new plateaus.
3. Step changes in behavior are the main driver in new plateaus.

So, to look at my example, preparing for (and running) a challenging two-day relay race in late April did cause a brief and significant loss in weight, but the pounds came back quickly over the following week, even exceeding the starting point. What did cause a lasting shift to the first new plateau was permanently cutting back my consumption of alcohol from 5 times to 2 times a week. Eating a big birthday dinner in June spiked my weight, during that phase, but the effect was transient. But what had a significant and lasting effect in July was increasing the frequency of my intermittent fasting from once a week (on average) to about 2-3 times a week. Most recently, I used an extended fast of between 2 1/2 to 3 days to reach my goal weight of 150 pounds, dropping 4 pounds from my last plateau of 154 pounds. I now realize that a single big move like that will not by itself produce a permanent change.  So my plan is to further extend my use of intermittent fasting so that I limit my eating to only 1 or 2 meals per day, going forward. So I will simply give up eating 3 meals a day; it will be either 1 or 2 meals (still giving me some freedom).  That may have seemed extreme several months ago.  But because I have approached this gradually, in small increments, I believe it will not be difficult at all.

The secret to plateau busting. To summarize, I think there are three important principles to keep in mind:

1. Make a deliberate, discrete step–and write it down! One of the most important aspects of this strategy is to define permanent changes based upon discrete quantum steps, not tiny moves along a continuum. For example, rather than gradually increasing the intervals between meals, make a one-time decision to cut out afternoon snacks. Or to skip lunches on certain days. Or add an extra workout each week. Write down the change on paper in clear language.  The value of doing this is that the change is conscious and deliberate, not something you slide into without awareness. Just as you pause on each boulder when crossing a stream and carefully plan your hop to the next boulder, be sure to deliberately and carefully plan each move to a new plateau, to be sure it is a step you think you can commit to. Look before you leap!
2. Keep records and establish a range of variation for each plateau. Any step to a new stable plateau is not a step to a fixed and unvarying behavior. There should be a certain range of “freedom”, allowing for natural variation. You will first need a little time after each change to “discover” what the new range of variation is. And the change will be more apparent if you are keeping good records of your weight, your speed, or whatever you are trying to change. (If you see no change within a week, you probably did not make a significant change). It’s best to chart the results graphically so that you can see the plateaus and the shifts. But once you see some results, it is equally important to establish firm limits to this range and stay within them.  In my last plateau, where my average weight dropped from 158 to 154 pounds, I was careful to stay in the range between 152 and 156 pounds.  Whenever I got close to the high end of the range, I consciously cut back on my eating to allow the weight to drift lower. I had just enough freedom to make this new plateau comfortable, but not enough to make it meaningless. Likewise I never pushed hard to get below 152 pounds during this period. These limits or bounds provide essential “habit separation” to isolate the new plateau or habit from backsliding into a previous plateau range.  Enjoy the freedom of the range, but strictly enforce the limits!
3. Allow yourself adequate time on each plateau. It is very important to allow yourself enough time to “get comfortable” at each new step. Don’t push too hard or move too quickly to the next step.  Habits take time to consolidate, both physiologically and psychologically. In the case of weight loss, what is really happening is that your hormones, enzymes, and other modulators of metabolism need time to re-balance, to provide the same level of homeostatic control of key energetic variables such blood glucose and fats as they did on the previous plateau.  If you are using intermittent fasting to lose weight, you must allow time to up-regulate the catabolic hormones and enzymes so that they can more readily mobilize fatty acids and glucose from storage, keeping your cells and your brain happy. This adaptation can take weeks, and you might be wise to stay on the new plateau for a few months!  Similarly, if you are adapting to lifting heavier weights or running faster miles, your body needs time to grow muscle tissue or increase aerobic capacity in response to the newly added stress. These changes are often imperceptible to you, but they are going on “behind the scenes”. To use the river-crossing analogy, allow time to catch your balance before you make the jump to the next boulder!  But don’t stay there forever…keep your ultimate goal in mind and make the next move when you feel ready.

Understanding that it takes time to adjust to a new plateau is, I think, a key point to being psychologically prepared to handle the inevitable resistance to change that is experienced whenever we “stretch” ourselves in the effort to grow physically, mentally or spiritually. Learning to appreciate your time on the plateau — even to love it — was one of George Leonard’s great insights that can help all of us who are on the path of change, as I discussed in another post about his book, “Mastery”. But the good news is that we don’t have to stay on a plateau forever, if we understand how it works. Armed with this knowledge, we can judiciously make our move to the next plateau in the right way and at the right time.

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Consider the following ten situations:

1. Drug addicts, before becoming addicted, experience the euphoria of a drug with few negative consequences. Over time, however, they develop a tolerance for the drug, requiring increasing doses to get the same high.  At the same time, their cravings and distressful feelings increase when going without the drug, leading to increased in withdrawal symptoms and a cycle of increasing drug use.
2. Firefighters and emergency room doctors have stressful jobs, but many find themselves experiencing an irresistible rush and heart-throbbing exhilaration from these fast-paced occupations.
3. New lovers, after a honeymoon period of initial infatuation, often experience a drop-off in affection, leading to dissatisfaction, fights, and sometimes breakups.  When reconciling after the breakup, they experience renewed closeness for a period of time. Typically, the more intense the infatuation, the greater the strife and negativity during the falling out periods.
4. Marathoners and other runners often experience a “runner’s high” which builds up during longer, more strenuous runs, and can extend for hours or even days after a run. Runner’s high has been associated with release of endorphins, a natural “opiate” produced by the body.
5. Infants who are given a bottle and start sucking on it experience pleasure.  But if the bottles are removed before the infants have finished feeding, they universally cry.  And yet they would not have cried if the bottle had never been given.
6. Depressed adolescents often resort to “cutting”, a form of self-mutilation that introduces some pleasure or even a high into their otherwise sad or pleasureless day.  They often find the need to increase the cutting to maintain the pleasure.
7. Scratching an itch generally relieves the itch and can be pleasurable, but often this ends up making the itch more intense and, after repeated itching, even painful.
8. Horror movies, which initially are disturbing or even terrifying, can become addictive
9. Politicians and executives in positions of power come to crave the power.  When they are out of the limelight, they experience a letdown, boredom, or even depression.  Upon retirement, this depression can lead to poor health or shortened longevity.
10. People who donate blood frequently report a sense of well being and pleasure that cannot be explained in terms of the blood removal itself.

Can you see the pattern?  In the odd-numbered examples above, pleasure turns to pain; in the even numbered examples, pain becomes pleasure. And in all cases, the effect intensifies with repetition. But why does this occur?  One possible explanation for these types of situation is described in William Irvine in his book “A Guide to the Good Life”:

The psychologists Shane Frederick and George Loewenstein have studied this phenomenon and given it a name: hedonic adaptation. To illustrate the adaptation process, they point to studies of lottery winners. Winning a lottery ticket typically allows someone to live the life of his dreams. It turns out, though, that after an initial period of exhilaration, lottery winners end up about as happy as they previously were. They start taking their new Ferrari and mansion for granted, the way they previously took their rusted-out pickup and cramped apartment for granted. (Irvine, p. 66).

Hedonic adaptation is the experience of “getting used to” a good or pleasurable thing until one returns to a state of relative indifference or equilibrium, feeling about the same as one did beforehand. As I describe in more detail on the Stoicism page of this blog, Irvine goes on to point out how the Greek and Roman Stoics were able to combat hedonic adaptation by practicing techniques such as “negative visualization”, in which they regularly took time to vividly imagine loss of people, relationships and possessions they held dear, so they could better appreciate what they had.

Hedonic reversal and habituation. While hedonic adaptation of this sort certainly exists, the ten situations I listed above are quite different than than that of the lottery winner that Irvine describes. My ten situations do not involve a return to homeostasis or equilibrium. They involve a total switch, what I will call hedonic reversal. Pleasure becomes pain; pain turns to pleasure. This is the phenomenon that Richard Solomon tries to explain in his paper.  Solomon quotes Plato, who may been the first to describe true hedonic reversal and puzzle over it:

How strange would appear to be this thing that men call pleasure! And how curiously it is related to what is thought to be its opposite, pain! The two will never be found together in a man, and yet if you seek the one and obtain it, you are almost bound always to get the other as well, just as though they were both attached to one and the same head….Wherever the one is found, the other follows up behind. So, in my case, since I had pain in my leg as a result of the fetters, pleasure seems to have come to follow it up.

In hedonic reversal, a stimulus that initially causes a pleasant or unpleasant response does not just dissipate or fade away, as Irvine describes, but rather the initial feeling leads to an opposite secondary emotion or sensation. Remarkably, the secondary reaction is often deeper or longer lasting than the initial reaction.  And what is more, when the stimulus is repeated many times, the initial response becomes weaker and the secondary response becomes stronger and lasts longer. This is what happens quite clearly in the case of addiction. After repeated administration, the original dose no longer gives the same high, so it must be increased to achieve that effect. In addition, as time goes on, abstaining from the addictive dose becomes more difficult, while cravings, anxiety and depressive feelings increase. The mirror image of this addictive pattern is apparent in the case of endorphin-producing athletic activities like running, or thrill-seeking pasttimes like parachuting. Solomon reports on a study of the emotional reactions of military parachutists:

During the first free-fall, before the parachute opens, military parachutists may experience terror: They may yell, pupils dilated, eyes bulging, bodies curled forward and stiff, heart racing and breathing irregular. After they land safely, they may walk around with a stunned and stony-faced expression for a few minutes, and then they usually smile, chatter, and gesticulate, being very socially active and appearing to be elated….The after-reaction appears to last about 10 minutes…After many parachute jumps, the signs of affective habituation are clear, and the fearful reaction is usually undetectable. Instead, the parachutists look tense, eager or excited, and during the free-fall they experience a “thrill”. After a safe landing, there is evidence of a withdrawal syndrome. The activity level is very high, with leaping, shouting…and general euphoria. This period, often described as exhilaration, decreases slowly in time, but often lasts for 2-3 hours. Indeed, I was once told by a sport parachutist…that his “high” lasted 8 hours. A new, positive source of reinforcement is now available, one that could never have eventuated without repeated self-exposures to an initially frightening situation to which the subject then becomes accustomed. (Solomon, pp. 693-8)

Thus, both the addictive pattern and the thrill pattern share the features of hedonic habituation (reduced intensity of the primary response) and hedonic withdrawal (heightened intensity of the secondary, opposite response). In surveying and studying a wide range of such experiences, Solomon found a common pattern of hedonic contrast, which he represented as follows:

baseline state → State A → State B

State A is the initial emotional or “affective” response to a stimulus, which can be either pleasant or unpleasant.  Typically, the first time a novel stimulus is applied, the primary or State A response is most pronounced at the outset and then tapers to steady level as long as the stimulus is maintained, as shown below in Figure 4.  For example, exposure to the heat of a sauna or hot tub may cause an initially hot or burning sensation, which diminishes somewhat over time. Once the stimulus is removed, the sensation is replaced by a contrasting sensation or affective state, the after-reaction, or State B.  State B is opposite in hedonic character to State A. If one is pleasant, the other is unpleasant, and vice versa. Initially, and after the first few stimulations, State B typically has a much lower intensity than State A, but often lasts longer in duration, before it eventually decays and returns to the baseline state.

What Solomon noticed is that after many repeated stimulations, the intensity of State A typically diminishes, both in peak intensity and steady state intensity. This is the hedonic habituation effect, also called “tolerance”, and it is seen with both pleasant and unpleasant affective reactions. The only way to increase the intensity of State A is to increase the magnitude of the stimulus. At the same time, with repeated exposures, the secondary affective State B often intensifies and lasts longer. This is the hedonic withdrawal effect. This combination of habituation and withdrawal effects is shown in Figure 5:  For addictions, the pleasurability of the stimulus diminishes with time and the unpleasant withdrawal grows in both intensity and duration. For the thrill-seeking or excitatory pattern, the stressfulness or unpleasantness of the stimulus is reduced with repetition, while the  ”withdrawal” becomes more pleasant and lasts longer, before returning to baseline.

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The opponent-process theory. So far, all we have presented is a qualitative description of some common patterns of sensory or emotional response, without any real explanation for why these patterns occur as they do. But Solomon’s real innovation is that he can explain these patterns by decomposing them into more elemental underlying biological processes. His central insight is that the nervous system is organized in such a way that any sensory or emotional response can be decomposed into two concurrent processes. The State A response diagrammed in Figures 4 and 5 above is in reality a composite of two complementary physiological processes:

• a primary process “a”, which is the direct observable response to the stimulus; and
• an opponent process “b”, which acts to inhibit or counteract the primary process.  It occurs at the same time as the primary process, but is not always evident or easy to perceive.

To understand how these processes actually work in practice, let’s look more closely at Figure 7 below. The opponent process “b” actually begins shortly after the initiation of the primary process “a” and acts to dampen it during what we observe as State A. Because “b” is both smaller and opposite in effect to “a”, it acts to reduce the net impact of “a”.  That explains why the intensity of the A process is greatest at the outset, but drops as the stimulus in continued.   According to Solomon, for a novel stimulus the “b” process is smaller and more sluggish than the “a” process.  It is slower to built to its steady state level (asymptote) and slower to decay after the stimulus stops.  This is shown in Panel A of Figure 7:

So what happens to bring about habituation after many repetitions of the stimulus, when the stimulus is no longer novel? According to Solomon, the primary “a” process remains unchanged in response to the stimulus.  What changes with repetition is the opponent process “b”.  As depicted in Panel B of Figure 7, after many stimulations:

• it intensifies
• it starts earlier (reduced latency period)
• it decays more slowly

The net impact of these changes in the opponent process is to progressively dampen the magnitude of State A and increase the speed, magnitude and duration of State B.  Thus, without any changes in the primary process, these changes in the opponent process can fully explain the increase in both tolerance and withdrawal, as shown in Figure 7.

Biological basis. Opponent processes are not just some clever hypothetical construct that Solomon came up with out of thin air. These kinds of inhibitory processes are common in biological systems.  For example, many or perhaps most neurotransmitters, hormones, and biological receptors have corresponding opposites, which act to inhibit or moderate the primary response. These inhibitory processes serve a useful biological control functions by preventing over-reactions to environmental disturbances. They form the the biological basis of systems of homeostasis, systems that enable organisms to resist or adapt to disturbances to their steady functioning.

Solomon’s opponent-process theory also identifies several key factors that can strengthen or weaken the opponent “b” process.  His paper summarizes some very clever animal research on distress behavior in ducklings, from which he deduced that the opponent process can be strengthened in three primary ways:

• increasing the intensity of the initial stimulus exposure
• increasing the duration of the stimulus
• shortening the interstimulus interval (the time between stimulus exposures)

Interestingly, merely repeating the stimulus, in and of itself, had no effect on strengthening of the opponent process if the stimulus was too weak or too short, or if the interstimulus interval was too long.  In particular, he found that, depending on the inherent duration of the opponent process, the interstimulus interval had a major effect on whether or not the opponent process will increase in strength.  According to Solomon

The critical decay duration is that disuse time just adequate to allow the weakening of the opponent process to its original, innate reaction level. If reinforcing stimuli are presented at interstimulus intervals greater than the decay duration, then the opponent process will fail to grow. (Solomon, p. 703)

Each opponent process has an inherent decay behavior, that is, a rate at which it fades away.  This will depend on the specific physiological and biological underpinnings of that process.  On a biochemical level, for example, this decay duration may depend on the half-life of the neurotransmitters, hormones, or receptor behavior involved.  It will surely also involve higher order processes which relate to the nervous system and psychological conditioning of the individual.  Figuring out the decay duration of various opponent processes should be a matter open to empirical determination.  It can be approached both by psychological investigations on others (or on oneself), and also by looking into the underlying physiological and biochemical mechanisms.

The final element of Solomon’s theory is a phenomenon he calls “savings”.  Although opponent processes can be weakened or faded away by avoiding the stimulus for an extended period of time, that does not mean they leave no memory traces. Studies show that these opponent processes are more quickly reactivated the next time they are re-stimulated. Reflexes and emotional reactions build up more quickly when reactivated than they did with the initial stimulation. According to Solomon,

Such a phenomenon is not unexpected. In alcohol addiction, for example, the abstainer is warned that one drink may be disastrous, and the reason is the savings principle. The reexercise of alcohol’s opponent-process system strengthens the withdrawal syndrome very rapidly and sets up the special conditions for resumption of the addictive cycle. Cigarette smokers report the same phenomenon: Readdiction to nicotine takes place much more rapidly than does the initial addiction. (Solomon, p. 703)

This savings effect also applies to positive opponent effects, such as the exhilaration experienced by skydivers or runners when resuming their thrilling or strenuous activities after a hiatus.  Understanding this effect is important in designing strategies for avoiding or minimizing the negative effects of relapse, as will be discussed below.

Put into simplest terms, the opponent-process theory explains the psychology of addiction and thrill-seeking in terms of the strengthening of inhibitory processes.  These inhibitory processes  get stronger when stimulation of a primary emotional response is sufficiently intense, sustained and frequent.  They become evident only when there stimulus and the primary processes are not present, and typically last for some time afterwards.   On subsequent re-exposure the stimulus, opponent processes often reactivated more quickly.

Is this a biologically realistic explanation?  Perhaps Solomon has not generated a broad enough set of hard physiological data to conclusively prove his hypothesis.  However, there is still a strong case in favor of it. First, his hypothesis provides a model which offers a coherent and consistent explanation for a wide range of  sensory and emotional behaviors for which there are few other good explanations. Second, there one application of the Opponent-Process theory–to an area unrelated to emotions–which has already been empirically verified:  the explanation of color perception. It is worth spending a paragraph on this because it provides some insights into the biological reality of this theory.

The opponent-process theory of color vision. Until the late nineteenth century, the primary theory of color vision was the trichromatic theory, which held that color perception was the result of the stimulation of three different types of cone receptors in the retina of the eye.  In 1892, Ewald Hering first proposed the opponent-process theory of color vision. He observed that any color can be uniquely analyzed in terms of the colors red, yellow, green, and blue, and noted that these four primary colors exist as the complementary pairs red-green and yellow-blue. Hering’s theory accounts for how the brain receives signals from different kinds of cone cells and processes and combines these signals in real time. The opponent-process theory of color vision received further support in 1957 in studies by Hurvich and Jameson, and in 2006 by Liapidevskii. Some of the most compelling evidence for the theory is the phenomenon of complementary color after-images, which cannot be explained by the tricolor theory.  You can demonstrate this for yourself by staring at the red dot in the middle of the image below for 30 seconds without letting your eyes drift from the center; then look at a blank white sheet and you will see the image with a more familiar set of colors. (It may take a while for the image to develop).

Looking at the colors under bright light and for longer periods enhances the opponent (inhibitory) processes in the receptors, which intensifies the after-images, just as one would predict based on the principles Solomon found for sensation and emotion.

Consider the similarity between this contrasting after-image response to visual stimuli and the emotional or affective responses that that Solomon found in his animal studies.  The sensory after-images may be less intense and of shorter duration, but the principle is the same, and both phenomena illustrate how opponent processes can arise within our nervous systems. Beyond the processing of simple nerve signals, such as those involved in visual sensory perception, the opponent process theory can account for psychological processes of increasing complexity and at multiple levels, based on the well established fact that the brain is able to integrate sensory information by adding and subtracting different excitatory and inhibitory inputs from different receptors and neurotransmitters.

Practical applications.  Besides explaining common sensory and emotional reactions, I believe the opponent-process provides some very practical guidance for how we can use pleasant and unpleasant experiences to our advantage.  This guidance can be boiled down to seven basic insights:

1. Be aware of hidden processes! The most important insight is to be aware that any primary sensory or emotional stimulus, whether pleasurable or unpleasant, will give rise to opponent processes of an contrasting nature.  Even though you most likely cannot directly perceive them, these opponent processes are happening–and even growing in strength–at the very same time as the primary emotions and sensations that you do perceive.  When the primary emotions and sensations stop or pause, these contrasting processes emerge into consciousness!  For example if you put your hand in cold water, a “warm” opponent processes is being stimulated, but you feel that warmth only once you withdraw your hand from the water. And the pleasure of overindulging in sweet desserts is likely to be followed by an unpleasant reaction that arises some time after you stop eating.
2. Avoid overexposure to pleasurable stimuli. This does not mean that you should minimize or avoid direct pleasure! Just be aware that too much of a good thing too often can backfire — and be aware WHY that is so. By remaining vigilant, you need only to moderate the intensity and frequency of pleasant stimuli to ensure that the opponent processes do not build up. For example, eating small portions of delicious foods, and spacing out meals — or even individual bites — will tend to reduce the level the opponent processes (cravings) that would otherwise reinforce appetite and cravings. When you go for that second cup of coffee, you may marginally increase your alertness in the short term, but realize that you are at the same time continuing to stimulate a reactive opponent process, counteracting the caffeine high, that may lead to increased tiredness later on.  There is a biological argument for moderation!
3. Use unpleasant and stressful stimuli to indirectly build pleasure. This is one of the most powerful insights of the opponent-process theory. By judiciously exposing ourselves to intermittent stresses, of sufficient intensity and frequency, we activate in our bodies and psyches some powerful opponent processes, which in turn result in heightened pleasure and satisfaction. Depending on the type of stimulus, these indirect pleasures can be short-lived or more sustained. Stressful or unpleasant stimuli can therefore be thought of as a form of “psychological hormesis”:  The nervous systems is activating certain pleasurable inhibitory processes in order to defend against and build tolerance to stress. These pleasure-generating defense mechanisms are real, biological processes which operate in our nervous systems. One well known example is the production of endorphins, our natural opiates, which can be produced by engaging in strenuous exercise. Endorphins literally help us to endure the pain of exercise by providing a counteracting pleasure. So by increasing the intensity and frequency of stress exposures, we are not just building tolerance–we are actively building up a sustained background “tone” of pleasurable emotions. This is very much in line with what the Stoics called “tranquility”. As explained on the Stoicism page, Stoic tranquility is not apathy or a lack of feeling!  On the contrary, it is a positive sense of equanimity, contentment, and happiness that endures and supports us.  It is the opposite of depression; you might even call it “elevation”.
4. Indirect pleasure is superior to direct pleasure. So we have learned that we can paradoxically use pain or discomfort to indirectly cause pleasure.  But is there any reason to think that the pleasure resulting from running, hard work, cold showers, or skydiving is superior to the pleasure from sweet desserts or scratching an itch? Aren’t they equivalent? Doesn’t any pleasure, whether direct or indirect, nevertheless have the potential to lead to addiction?  This is an interesting question, but I think the opponent-process theory makes the case that indirect pleasures — those that results as reactions to stress — are superior. There are two main reasons for this:  First, according to Solomon, opponent-processes are “sluggish”; they take time to build, and decay more slowly. They continue even when the stimulus stops. And unlike direct pleasures, which may be more intense, there is no sudden withdrawal reaction when they stop, hence no “craving”. They tend to fade slowly. Second, the initial unpleasant stimulus — exercise, work, cold sensations — must be sufficiently unpleasant to be effective. This initial unpleasantness will always be a “barrier” that requires conscious effort to face and overcome. If it starts to become “addictive”, it is easier to let this unpleasant barrier stand in the way. It is easy to decide not to go running or take a cold shower if one becomes concerned it is becoming too habit-forming or detrimental to one’s health.
5. Use unpleasant stimuli to counteract addictive pleasures. This is one of the most interesting, and I think unexplored, applications of the opponent-process theory. Addictions are characterized by increased cravings. These arise when opponent process build up in reaction to pleasurable primary stimuli that are too intense and frequent. The craving can become a sustained background “tone” that is always there when the pleasurable stimulus is absent. And the “savings” effect makes the opponent cravings come back more easily. But we can overpower these cravings by deliberately introducing unpleasant stimuli at the same time as the addictive cravings, in order to generate new pleasurable opponent processes. The key is to time the unpleasant stimuli to coincide with cravings or withdrawal, and make them sufficiently intense and frequent, that one builds up sufficient background pleasure tone to counteract the unpleasant anxiety that typically accompanies addictions. So fight cravings by adding a new stressful activity like high intensity exercise, cold showers, or intermittent fasting! It may also help explain why cue exposure therapy — exposing oneself to the forbidden fruit without partaking — can often be more effective in extinguishing addictions than merely abstaining or avoiding the addictive stimulus. It is possible that active cue exposure might generate a type of acute “stress” that “burns out “the original craving with an opposing pleasure. This is like fighting fire with fire!
6. Don’t abuse pain and stress. Despite the potential benefits of controlled stress and unpleasant stimuli to indirectly induce sustained pleasure or “elevation”, this approach is easy to misinterpret or apply incorrectly. Some might take this to be a justification for masochism or self-harm, but it is not. The key here is to carefully think through the consequences of one’s actions. Does the application of the stress or unpleasantness result in an objective strengthening of your body and mind — or does it lead to physical or psychological harm?  Depressed teens sometimes engage in a practice called “cutting” to relieve their depression and apathy, because it can actually reactivate pleasure or a rush that fills a gap and can become addictive. Most likely, this pleasure can be explained in terms of opponent processes that release some of the same endorphins or other neurotransmitters as exercise does. But one needs to distinguish between objectively harmful activities like cutting and beneficial habits like exercise or cold showers. Far from injuring oneself, these beneficial uses of stress and “pain” act to act to build strength, resilience, and long-term happiness.
7. Optimize your stimulation schedule. Be aware of critical decay durations and savings effects of opponent processes, for both pleasant and unpleasant stimuli. Addictions and cravings can be minimized by reducing the frequency of exposure to pleasure-triggers to allow enough time for any cravings to decay. The next time you are mindlessly wolfing down bite after bite of an addictive snack like popcorn or candy, try spacing out bites to allow the craving sensations to die off between bites and see whether you end up satisfied with fewer bites. On the flip side, if you are finding it hard to get started on a healthy habit like strenuous exercise, cold showers, or fasting, it may be that you need to increase the frequency and intensity of the new habit until it takes. According to Solomon, it will become increasingly pleasant if you do this.

Since becoming aware of the opponent-process theory, I applied it to myself in two instances recently:

• On the pleasure side, I reduced my craving for alcohol by drinking less frequently, and limiting the amount that I drink.   The pleasure remains, but the daily cravings have disappeared. I’ve documented this on the Discussion Forum of this blog.
• On the pain side, I have increased my enjoyment of cold showers by never missing a day, by lengthening the showers, and by making sure to expose my most sensitive body parts to the coldness.  This has significantly increased the pleasure I feel, and it comes on more quickly while in the shower (within 10-15 seconds, versus previously more than a minute) and the warm, exhilarating post-shower feeling lasts all morning.  I’m happy all the time, and I definitely feel less stress.

Think about how this might apply to your own situation. Are there pleasures in your life that tend to result in cravings when they are absent? Can you think of ways to introduce healthful but somewhat unpleasant stress into your life in a way that builds your resilience and at the same time a deeper level of satisfaction and sustained pleasure?  Can you use this indirect pleasure to displace cravings or dissatisfaction? And in both cases, how aware are you of the relationship between the intensity and frequency of the stimuli, and the tendency to foster opposing processes that turn pleasures into pains, and pains into pleasures?

The potential applications are infinite!

The starting point of Mastery is that we live in a culture at war with the proper understanding of mastery. From movies, commercials and popular culture, we tend to see life as an uninterrupted series of successful climaxes, without consideration of the effort, pauses, or setbacks that will be inevitably encountered.  We expect a certain level of excitement and interest in any experience, or we become quickly bored. We adopt a quick-fix and bottom-line mentality. In our work life and even at home, we are told to set goals, to measure our advances, and to expect continuous progress towards our goals. And even happiness itself is defined in terms of reaching those goals.

Presciently, Leonard also noted that this “antimastery” attitude applies not just to us as individuals, but as a nation.  Keep in mind that these words were written almost two decades before the recent global financial crisis:

Our present national prosperity is built on a huge deficit and trillions of dollars worth of overdue expenditures on environmental cleanup, infrastructure repair, education, and social services–the quick fix mentality. The failure to deal with the deficit goes along with easy credit and the continuing encouragement of individual consumption at the expense of saving and longer term goals…But our time of grace might be running out. In the long run, the war against mastery, the path of patient, dedicated effort without attachment to immediate results, is a war that can’t be won. (Mastery, pp. 36-37).

Leonard portrays common attitudes towards attempting to master new skills or challenges in the guise of three personas.  These character types are to some extent caricatures, but if you think about, you may find within yourself one of them.  Which one best describes you?

1. The Dabbler, who approaches each new sport, hobby, job opportunity or relationship with enthusiam, but loses interest once initial progress slows or a setback is encountered.  Then it is on to the next interest.
2. The Obsessive, who is intensely goal-oriented and results-focused, and pursues mastery with intensity and dogged persistence, making rapid initial progress.  When setbacks are encountered, the Obsessive redoubles the effort and pushes forward without mercy. But because this cannot be sustained, ultimately the crash comes and burnout follows.
3. The Hacker, who is much more laid back about learning new things than the Dabbler or Obsessive, and is content to stay on the plateau indefinitely, just “hanging out” in a certain comfort zone. The Hacker does avoid getting frustrated, but at the same time is unwilling to invest real effort and hard work in the practice, never pushing, and never really progressing.

For Leonard, mastery is not about reaching perfection, but rather comes from maintaining a particular mindset as you move along the path of improvement in building your skills or overcoming challenges in any endeavor.  He adeptly describes the “mastery curve” :

Learning any new skill involves relatively brief spurts of progress, each of which is followed by a slight decline to a plateau somewhat higher in most cases than that which preceded it…the upward spurts vary; the plateaus have their own dips and rises along the way…To take the master’s journey, you have to practice diligently, striving to hone your skills, to attain new levels of competence. But while doing so–and this is the inexorable–fact of the journey–you also have to be willing to spend most of your time on a plateau, to keep practicing even when you seem to be getting nowhere. (Mastery, p. 14-15).

This fact of devoting much of your time on plateaus or even backsliding may be frustrating or dispiriting if you are hellbent on bottom-line progress. But the person on the path of mastery not only acknowledges the plateau, he embraces it and learns to love “practice” for its own sake and rewards. I think this advice can be of great help to those of us struggling with plateaus in the effort to get fit, lose weight, or advance in other ways.

It’s hard to select just a few of the lessons from such a rich and wise book.  Because Leonard is a talented writer, instead of paraphrasing him, I’ll pick quotes from four chapters that I think are especially useful for working to improve your strength in any chosen endeavor.

Chapter 6: Practice

To practice regularly, even when you seem to be getting nowhere, might at first seem onerous. But the day eventually comes when practicing becomes a treasured part of your life….Ultimately, practice is the path of mastery. If you stay on it long enough, you’ll find it to be a vivid place, with its ups and downs, its challenges and comforts, its surprises, disappointments, and unconditional joys. (Mastery, p. 79)

Chapter 7: The Edge

The trick here is not only to test the edges of the envelope, but to walk the fine line between endless, goalless practice and those alluring goals that appear along the way…Playing the edge is a balancing act. It demands the awareness to know when you’re pushing yourself beyond safe limits. In this awareness, the man or woman on the path of mastery sometimes makes a conscious decision to do just that. We see this clearly in running, a sport so pure, so explicit that everything comes into full view…Many people run not to lose weight but to loosen the chains of a mechanized culture, not to postpone death but to savor life. (Mastery, pp. 99-100).

Chapter 10: Why Resolutions Fail–and What to Do About It

Backsliding is a universal experience. Every one of us resists significant change, no matter whether it’s for the worse or for the better. Our body, brain and behavior have a built-in tendency to stay the same within rather narrow limits, and to snap back when changed…Be aware of the way homeostasis works…Expect resistance and backlash. Realize that when the alarm bells start ringing, it doesn’t necessarily mean you’re sick or crazy or lazy or that you’ve made a bad decision in embarking on the journey of mastery. In fact, you might take these signals as an indication that your life is definitely changing–just what you’ve wanted….Be willing to negotiate with your resistance to change. (Mastery, p. 107-115).

Chapter 13: Mastering the Commonplace

Our preoccupation with goals, results, and the quick fix has separated us from our own experiences…there are all of those chores that most of us can’t avoid: cleaning, straightening, raking leaves, shopping for groceries, driving the children to various activities, preparing food, washing dishes, washing the car, commuting, performing the routine, repetitive aspects of our jobs….Take driving, for instance. Say you need to drive ten miles to visit a friend. You might consider the trip itself as in-between-time, something to get over with. Or you could take it as an opportunity for the practice of mastery. In that case, you would approach your car in a state of full awareness…Take a moment to walk around the car and check its external condition, especially that of the tires…Open the door and get in the driver’s seat, performing the next series of actions as a ritual: fastening the seatbelt, adjusting the seat and the rearview mirror…As you begin moving, make a silent affirmation that you’ll take responsibility for the space all around your vehicle at all times…We tend to downgrade driving as a skill simply because it’s so common. Actually maneuvering a car through varying conditions of weather, traffic, and road surface calls for an extremely high level of perception, concentration, coordination, and judgement…Driving can be high art…Ultimately, nothing in this life is “commonplace,” nothing is “in between.”  The threads that join your every act, your every thought, are infinite.  All paths of mastery eventually merge. (Mastery, p. 141-150).

These last words by Leonard about mastery of the commonplace are among my favorite.  Reading this chapter led me to see things in a new light, to slow down, to deliberately take more time and be more patient getting through the day. Obstacles such as getting stuck in traffic or encountering angry or irritating people are no longer seen as frustrations, but rather opportunities for practicing our skills of calmness, persistence, kindness, and good humor.  Peforming daily tasks, with care, responsibility and in “good form” also resonates with the Hormetic principle of “constraint”, or practicing without cheating or compromising in form, so as to train the correct behavior.

Leonard’s advice that we pay careful attention to the quality of our actions and attitudes in everyday tasks, brings to mind the perspective of the ancient Stoics that we should concentrate our focus on “internals” — the character of our thoughts and actions, the things in life over which we have the most control.  By contrast, the Stoics considered “externals”–our dealings with others and the world around us–as not so very significant in and of themselves, and as not fully within our control.  Externals were to be considered merely as “materials” or opportunities for us to demonstrate and perfect our character–to master ourselves. And in fact, plateaus in our progress can be thought of as an excellent example of externals that are thrown at us.  These give us an opportunity to test our stoicism and sharpen it. Just as we can increase our physical strength by testing ourselves against progressively greater physical stresses, we can become emotionally and spiritually stronger by adopting Leornard’s attitude towards mastering the commonplace, by welcoming every challenge as a chance to get better at living life.

Does this ring true in your own attempts at mastery?