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.

It is because I’ve found intermittent fasting to be an attractive practice, both scientifically and personally, that I was so excited to be invited to give a lecture on IF at The 3rd Door, an innovative health and fitness studio, cafe and social center in downtown Palo Alto. The fitness director at The Third Door, Johnny Nguyen, is himself an advocate and practitoner of IF, which he blogs about with great flair and common sense at The Lean Saloon. The talk gave me an opportunity to reframe intermittent fasting in the terms of the philosophy of Hormetism, or applied hormesis that I write about on this blog.  I believe that the framework of hormesis helps to make sense of why IF works, and why it is so much more than a diet.

What follows is a video of my talk on the benefits of intermittent fasting, presented on May 18, 2011 at The 3rd Door.  I would like to thank Dianne Giancarlo and Johnny Nguyen for inviting me to speak, Vaciliki Papademetriou for technical assistance, Francesca Freedman for introducing me to The Third Door, Tom Merson for the still photos and Ken Becker for the masterful video production.

The talk is divided in to five sections for ease of viewing.  It was followed by a 30 minute question and answer session, which I will upload as soon as the video production is complete:

Part 1:  The benefits of calorie restriction

Part 2:  Calorie restriction and hormesis

Part 3:  Intermittent fasting and diet myths

Part 4:  How intermittent fasting turns you into a “flex fuel vehicle”

Part 5:  Practical advice on how to get started with intermittent fasting

Within the coming week, I will add here a recording of the 30-minute question and answer session following the talk.

If the above talk was of interest, you can find more detailed information in two of my other posts:

• Calorie restriction and hormesis
• Learning to fast

Happy fasting!

Whether or not insulin is to blame for the obesity epidemic is one of the hot questions being debated on heath and diet blogs.  On the surface, this seems like an arcane question that would mainly interest physiologists and diet researchers.  After all, who really cares about the underlying mechanisms of fat storage and release?   Most of us just want to know some practical steps we can take to lose excess weight and keep it off and, beyond that, to stay healthy.

It seems like a simple yes-or-no question of fact that you could settle by studying populations and doing lab studies. But it’s not so much a question about facts as one about causation.  Questions of causation are often the thorniest ones. This particular question has taken on almost political or religious overtones, provoking emotion and acrimony in the diet blogosphere. On one side are defenders of the Carbohydrate/Insulin Hypothesis, like Gary Taubes and Michael Eades.  This is laid out in detail in Taubes’ book  Good Calories, Bad Calories (2007), and more compactly in “Why We Get Fat: And What To Do About It” (2010). On the other side are opponents such as James Krieger and CarbSane, who find the Carbohydrate/Insulin Hypothesis to be oversimplified and deeply flawed, citing recent scientific advances. People tend to chose up sides in this debate.  I’ve been participating in this debate myself (while still learning a lot) on the websites of Jimmy Moore, James Krieger, and CarbSane. I won’t rehash all the technical details here. Instead, I’d like to propose a “frameshift” that recognizes and integrates the strong points from each side, attempting to overcome their shortcomings.

First, here’s an overview of what each side has to say:

Proponents of the Carbohydrate/Insulin Hypothesis, as articulated by Taubes, posit four main points:

1. Obesity is a disorder of excess fat accumulation, not voluntary overeating or inactivity, caused by an imbalance in hormonal regulation of adipose tissue and fat metabolism.
2. Insulin is the primary regulator of fat storage.  When insulin levels are elevated–either chronically or after a meal–we accumulate fat in adopose tissue.  When insulin levels fall, we release fat and oxidize it for fuel.
3. Elevated blood insulin levels increase hunger and the drive to eat, while decreasing energy expenditure and activity
4. By stimulating insulin secretion, carbohydrates make us fat and ultimately cause obesity

In short: Carbohydrates drives insulin, which drives fat.

Opponents of the Carbohydrate Hypothesis challenge each of the above points.  I’ve paraphrased four main counterpoints here:

1. Fat accumulation and obesity result from positive caloric balance (more calories consumed than expended), without regard to the macronutrient class of calorie (carbohydrate, protein, or fat).
2. Your body can store fat even when insulin is low, via the action of the hormone ASP (acylation stimulating protein)
3. Insulin doesn’t make you hungry; rather, it suppresses appetite. (The critics proffer that low carb diets may work because protein is more satiating than carbohydrates, but they merely report this observation and don’t attempt to explain it).
4. Carbohydrate doesn’t uniquely stimulate insulin; many proteins are equally or more insulinogenic.

In short: Calories in minus calories out drives fat.

On the surface of it, these two models of fat metabolism appear to be diametrically opposed.  But are they really?  There is at least one large point on which both sides appear to agree:

Obesity, particularly of the abdominal type, is associated with insulin resistance.

What that means is that people with abdominal obesity (the characteristic “apple” or pot belly shape, rather than those with “pear” shaped backsides or extra subcutaneous fat)  tend to secrete more insulin after eating and have high basal insulin levels, ultimately leading to elevated blood glucose, triglycerides, elevated blood pressure, unfavorable cholesterol ratios, and a host of other issues associated with metabolic syndrome or “Syndrome X”.  Nobody seems to deny this. Sometimes leptin resistance is also cited as an independent or alternative marker of obesity.  But I’ll focus here primarily on insulin resistance, because it seems to be more closely involved with regulation of nutrient partitioning than is leptin.

Where the two sides disagree,  however, is on the causal chain behind the association between obesity and insulin resistance.  Advocates of the carbohydrate/insulin hypothesis tend to arrange the causal the order, from causes to effects, as:

carbohydrates > insulin spikes > hyperinsulinemia > insulin resistance > obesity

Whereas Krieger and CarbSane argue that the order of causality should be:

positive caloric balance > obesity > insulin resistance > hyerinsulinemia

When you look more deeply, however, there is acknoweldgement on both sides that insulin resistance is not a simple monocausal condition, but is likely multifactorial.  There is evidence of many contributing factors, including:

• specific dietary components: fructose, sucrose, saturated fats, gluten, lectins, dairy, allergens
• micronutrient deficiencies: vitamin D, magnesium, omega-3 fatty acids
• metabolites:  triglycerides, free fatty acids (“FFA”, also called non-esterified fatty acids or “NEFA”)
• inflammatory conditions
• lack of physical activity and exercise (particularly strenuous exercise)
• genetics

There is as yet no broad scientific consensus as to the relative importance of each of these factors in causing insulin resistance. But it is almost certain that there is no single cause.  Regardless of the cause, however, it is important to understand what insulin resistance is on a cellular level: a reduction in the number and sensitivity of insulin receptors, such as GLUT4 receptors.  Different tissues can experience different degrees of insulin resistance.  Typically, muscle tissues are the first to become insulin resistance and fat tissue is one of the last.  Insulin resistance in different organs like the brain or the skin can have different effects.  Some have argued that certain pathologies such as Alzheimer’s disease and acne are associated with organ-specific insulin resistance. I’ve proposed elsewhere on this blog (“Change your receptors, change your set point“) that receptor number and sensitivity can serve as a kind of dynamic “set point” for weight and other physiogical states governed by hormone-receptor and neurotransmitter-receptor balances.

So here is where I think that a frameshift in the debate about insulin can reconcile the two sides, at least in good measure:

Insulin resistant (IR) individuals respond in a qualititatively different way to carbohydrates and fats in their diet.

Let’s see what that means specifically:

First, consider insulin resistant (IR) individuals, regardless of how they got that way.  IR individuals have elevated basal insulin levels, usually defined as a fasting insulin of at least 15 μIU/mL, or perhaps higher.  If you have a protruding belly, high triglycerides and a high blood pressure, you are probably in this category.  Under these conditions, dietary carbohydrate, and to a lesser extent protein, add fuel to the fire by spiking an already elevated insulin level. And let us grant here the point of Krieger and CarbSane that ASP is a potent faciliator of fat storage.  It is known than insulin significantly enhances the action of ASP.  In addition, insulin upregulates lipoprotein lipase (LPL) a fat-storage  promoting enzyme and inhibits the action of hormone sensitive lipase (HSL) an enzyme that favors hydrolysis of stored lipids to free fatty acids.  Combine all three effects and we should expect that IR individuals store dietary fat easily, even with moderately low carbohydrate diets.

For these individuals, the elevated levels of basal insulin will tend to shift the balance of glucose and fatty acids from the blood stream into the tissues.  (Krieger and CarbSane are correct that insulin may not play a big direct role in driving fat sequestration, but its indirect stimulatory effects on ASP and LPL and inhibitory effect on HSL are quite significant, reducing the concentration of fatty acids in the blood stream by shifting the equilibrium towards the adipocytes).  This will also tend to stimulate appetite and eating, leading to more fat storage and a worsening IR condition. Sugarholics and those with carbohydrate cravings tend to be insulin resistant. Appetite has a large conditioned component, whereby preprandial levels of insulin, ghrelin, and other hormones are secreted based upon temporal cues and specific sensory cues.  It has been found that this pre-prandial secretion is much more pronounced in overweight, IR individuals.

One of the best ways to break this cycle is to go on a very low carbohydrate diet, something like the Atkins induction diet.  Since there is no insulin response to dietary fat, a high fat, very low carb, moderate protein diet will allow basal insulin level to gradually drift down.  This will shift the balance, reducing (but not eliminating) the actions of ASP and LPL, and disinhibiting the action of HSL. This will increase release of glucose and fatty acids, supplying energy and providing satiety, further lessening the drive to eat.  The vicious cycle is replaced by a virtuous one. Unfortunately, a reduced calorie, high carb diet will not work for IR individuals, because their appetite is so easily triggered by any increase in insulin, which leads to a faster than normal drop in blood glucose.  Note that blood glucose does not have to be “low” to induce hunger.  There is evidence that hunger is triggered merely by a rapid drop in glucose levels.   On the Deconditioning Diet page of this blog, I describe a method for extinguishing this conditioned pre-prandial insulin response.

Claims that insulin suppresses appetite is based on studies involving central administration of insulin while artificially infusing glucose. Krieger is correct about the “central” effect of insulin within the hypothalamus and upon the vagal afferent fibers. However, as with many hormones, insulin can have opposing effects at different locations and times. We need to consider the important appetite-inducing effect of insulin secreted into the “periphery”, without the simultaneous supplementation of glucose or other nutrients.  This is a particular issue for IR individuals who are vulnerable to insulin-induced cravings, and less of an issue for those with good blood sugar control.

Now let’s consider insulin sensitive (IS) individuals. These are people with less than 10 μIU/mL, ideally less than 5 μIU/mL insulin.   The situation is quite different for these folks.  As a result of much lower basal insulin levels, they have more stable blood glucose and fatty acid levels, because the lower insulin levels reduce inhibition of glucose and fatty acid release from glycogen and adipose tissue.  So IS individuals are less prone to hunger cravings, because they can access their own energy stores more easily. They are much better able to tolerate higher levels of carbohydrate in the diet, because their insulin response is well controlled and glucose readily gets to the cells and brain after eating.

This may also provide a plausible explanation for why certain populations such as the Okinawans, the Kitavans, and other cultures remain lean on a relatively high carbohydrate diet:  their low basal insulin levels and high insulin sensitivity permit them to handle carbohydrates easily.  According to Stephan Guyunet’s Whole Health Source blog:

Grains, refined sugar, vegetable oils and other processed foods are virtually nonexistent on Kitava. They get an estimated 69% of their calories from carbohydrate, 21% from fat, 17% from saturated fat and 10% from protein. Most of their fat intake is saturated because it comes from coconuts. They have an omega-6 : omega-3 ratio of approximately 1:2. Average caloric intake is 2,200 calories per day (9,200 kJ). By Western standards, their diet is high in carbohydrate, high in saturated fat, low in total fat, a bit low in protein and high in calories.

While this is a “high carbohydrate” diet, the carbohydrates are not typical western foods: The Kitavan diet consists mainly of foods like tubers, fruit, coconut, fish and vegetables. Even with the high carbohydrate levels, their insulin levels are much lower than that of typical Westerners.  One could argue that these foods have low levels of fructose and sugars, and are generally quite non-inflammatory, so they should promote insulin sensitivity.  According to Lindeberg, their fasting insulin levels averaged 3.12 and 3.29 IU/ml for males and females, respectively.  This is about half the basal insulin levels of Swedes: 6.98 and 6.65 IU/ml for males and females, respectively. Fasting blood glucose levels for the Kitavan’s were about 27% lower than that of the Swedes.

Furthermore, IS individuals should be able to lose fat quite easily by restricting carbohydrate, intermittent fasting and/or exercise. With resulting very low basal insulin levels, it should be even easier to release fat from adipose tissue and oxidize it for energy, or to go into ketosis. It is known that Type 1 diabetics, who have no insulin, shed fat readily and have trouble holding onto it without injections.  But someone with low basal insulin can achieve a naturally lean state easily, while also being able to handle insulinogenic meals without difficulty.  Based on my own experience over time, as my fasting insulin level has dropped, intermittent fasting and even fasted workouts become easy, and this does not preclude a reasonable level of carbohydrates in my diet.

Now let’s ask the question of whether insulin sensitive (IS)  individuals can accumulate body fat on a high-fat, low carb diet. According to Krieger and CarbSane, this should be no more difficult than on a high-carb diet.  You just have to eat a “caloric surplus” of fat, with no or little carbohydrate, and ASP will do the job, even without insulin.  But will this really have the predicted effect?  Without doing the study, it is hard to know for sure.  But my prediction would be that it is unlikely to play out as they suggest, for several reasons:

1. Despite the claims that ASP works without any insulin, the primary sources don’t show this. For example in the paper by Saleh et al., which CarbSane cites in support, there is still some insulin and carbohydrate present to stimulate ASP, with or without the action of chylomicrons.
2. Even assuming that the ASP could drive fat accumulation without insulin present, the lack of insulin would also favor downregulation of LPL and activation of HSL, which will tend to balance ASP’s action by liberating fatty acids from the adipocyte.
3. Under low insulin conditions, even with excess fatty acids being fixed within the adipocytes, one would expect a reasonably high equilibrium level of free fatty acids in the blood stream.  This would favor satiety, so that eating the fat meal would be self-limiting.  This contrasts with the action of insulin which, when elevated, will tend to deplete the blood stream of glucose and fatty acids.

I will conclude with the following synthesis between the above opposing positions:

So the answer to the question is to shift the blame from the hormone insulin to the condition of the insulin receptors.  Insulin spikes at meal time are no problem, so long as basal insulin remains low. Restriction of dietary carbohydrate is one very effective strategy, which should be chosen not for the short term benefits in weight loss, so much as the longer term benefits in improving insulin sensitivity and reducing basal insulin.  With the focus on “regrowing” and “reconditioning” insulin receptors, we should look at the full arsenal of tools, including intermittent fasting, nutrients such as vitamin D, magnesium and fish oil, and high intensity interval training.

Let me emphasize here that my proposed explanation is meant as a tentative conceptual framework rather than a conclusive scientific analysis.  I’m still learning about the details and I fully expect that our understanding of the underlying mechanisms of fat metabolism will continue to be revised and evolve.  But I do think that there has been too much emphasis placed on hormones and neurotransmitters, which fluctuate every day,  and not enough on receptor health, which is something we can can influence over the long term by commitment to scientifically informed practices.

If you are interested in this general framework for diet and how it fits into my overall philosophy of Hormetism, check out my podcast interview with Jimmy Moore which just went live today.

One of the most common reactions I get to my advice to try intermittent fasting is:  I could never do that!

Like the Jackson Browne song “Running on Empty,” the word “fasting” often conjures up dire images of starvation and energy deprivation.  Many of you reading this post may have experienced strong hunger pangs, headaches, tiredness, sweating and even shaking or wooziness when going without eating for even part of a day, much less a whole day.  So it is natural to extrapolate such experiences into the thought that going without food for a day, or even several hours, would invariably lead to uncomfortable or even dangerous hypoglycermic symptoms. That, together with the negative image of fasting as something unhealthy or associated with eating disorders, leaves most people pale at the thought of even attempting a short fast.

But I tell you, if you don’t try fasting you are missing out on an enjoyable, incredibly energizing experience that will put you in control of your eating and improve your health, your energy and your outlook.  Many people, myself included, have learned to fast for up to a day or even longer, on a regular basis and without negative repurcussions. Done correctly, short-term fasting is not dangerous, it’s actually health-promoting and greatly helps to retrain your appetite.  If you need to lose weight, the fast helps both in reducing basal insulin and retraining your appetite to be smaller. I’ve written about the benefits of intermittent fasting extensively on this site. Many of the Diet Links listed in the right-hand panel, such as fast-5 and Eat-Stop-Eat, amply document the safety and health benefits of fasting, dispelling the myths about “starvation mode”, slowing of metabolism,  and loss of lean muscle mass.  So I won’t reiterate here the voluminous evidence supporting the benefits of intermittent fasting.  Our bodies are designed to last many days with out food, without great discomfort, and in fact it is beneficial to our health to forgo food periodically. But many of you are asking: Am I really up to this?  How do I get started?

To clarify, by intermittent fasting (IF), I mean forgoing eating for at least 12-20 hours in a day, at least one or two days each week. For many of us, it is a daily practice. Water and unsweetened, non-caloric beverages are allowed, but I exclude “juice fasting” or any solid snacks from true fasting. Others have written about the virtues of juice fasts for “detox” or “cleansing”, but IF has a different purpose, namely insulin reduction, appetite reduction, and mental clarity and focus.

Tips for getting started. So this post is not about the benefits of intermittent fasting, but rather about how to get started with it.  I’m basing this largely on my own personal experience, combined with what I’ve learned about what has worked for others. Fasting is not that hard or unpleasant to do. The reality is that, like skydiving, the contemplation of it is probably far worse than the experience.  You will experience some periods of discomfort, but you may be surprised at how great you’ll feel most of the time you are fasting, especially once you are past the first few hours.  People on low carbohydrate diets often (but not always) experience the pleasurable energy that comes with ketosis; I’ve found that the ketosis of fasting is deeper, and more reliable that that from low carb.  Several people who experience brain fog on low carb  find fasting to provide greater clarity and energy.

Here are 7 practical suggestions to help you get through the transition:

1. Start with a mini-fast. How long do you go between meals without eating? Two hours? Five hours? Start there and try to increase it by a few hours. The easiest way to start is to cut out eating anything between dinner and bedtime. Then go to cutting out afternoon snacks 2 or 3 days a week. And increase from there in increments. Of all my suggestions, I think this is the most important. It’s one of the core principles of using Hormetism to improve your strength and resilience in any challenging endeavor. You have to walk before you can run.

A very common mistake that many people make when embarking on fasting is to go straightaway from a typical pattern of 3 meals per day with snacks, to a day-long fast.  That’s a terrible idea, and yet it forms the main reason that so many people reject fasting as impractical or unhealthful.  I’ll repeat here the comments I made in an earlier post on Calorie restriction and hormesis about a researcher’s conclusions in a 2006 study of calorie restriction in mice, in the journal Biogerontology:

Calorie restriction is doomed to fail, and will make people miserable in the process of attempting it,” said Dr. Jay Phelan, an evolutionary biologist at the University of California, Los Angeles, and a co-author of the paper. “We do see benefits, but not an increase in life span.” Mice who must scratch for food for a couple of years would be analogous, in terms of natural selection, to humans who must survive 20-year famines, Dr. Phelan said. But nature seldom demands that humans endure such conditions. Besides, he added, there is virtually no chance Americans will adopt such a severe menu plan in great numbers. “Have you ever tried to go without food for a day?” Dr. Phelan asked. “I did it once, because I was curious about what the mice in my lab experienced, and I couldn’t even function at the end of the day.

It’s not surprising that Dr. Phelan’s personal “one day experiment” failed and that he “couldn’t function” after suddenly downshifting gears so rapidly. As anyone who has taken the time to research calorie reduction or intermittent fasting realizes, a dietary change of this sort should be approached gradually, allowing time for deconditioning of previous dietary habits and hormonal responses. These changes typically take weeks or longer to become comfortable. But that does not mean that a reduced calorie diet is “extreme”. By historical standards, it would be more accurate to characterize the typical hypercaloric American diet as extreme.

2.  Schedule your fasts. Intermittent fasting works best when you are in control of the timing.  I like being able to spontaneously decide when I’ll start my next fast and I plan exactly when I’ll break the fast and eat.  That really frees me from thinking about food and making choices, because I know that at 4 p.m. Friday or noon Sunday I’ll have my next meal. Associating the start and stop of a planned fast with definite events or times of day takes advantage of the well-known behavioral principle of “putting on cue”.  For a fuller explanation, check out the work of Karen Pryor, the renowned animal behaviorist and dolphin trainer.  I’ve also written about this on the Psychology page of this blog.

3. Cheat using high fat “training snacks”. If you’re having trouble fasting, it is likely that you are lacking the ability to readily shift to fat burning and ketosis.  When you are fasting, after initially depleting your glycogen stores, you will be literally “living off your fat”, as well as fat byproducts like ketones.  To do that, you’ll need to get your insulin level very low and upregulate your catabolic hormones and enzymes: glucagon, adrenaline and hormone sensitive lipase.  But if you are used to eating 3 or more meals and snacking frequently, then you are not used to metabolizing your own fat stores, and you have difficulty shifting quickly from energy storage (anabolism) to energy release (catabolism) .  You literally have weeks of “meals” stored beneath your skin and within your abdomen.  You just can’t access them.  It’s literally like having a locked pantry on your body, so when you get hungry you have to eat food supplied externally, instead of what is already within you.

So train yourself to burn fat by eating pure fat or oil!  The easiest way to train your body to get it used to burning fat, is to “jump start” it with a small high-fat “training snack”.   You don’t need much to get started: 5 to 10 grams of fat is plenty.  Don’t worry, this is not a “high fat diet”, it serves only to provide some satiety and let your metabolism get used to fat burning. The amount of fat you’ll snack on is trivial compared to your overall weekly diet, and you’ll go back to your “normal” diet after the fast. The best approach is to wait until you would normally have a meal or snack and substitute the high fat training snack.  This will tend to suppress your appetite for at least a few hours.  If you start to get hungry again, take another training snack — but wait at least 3-4 hours between these snacks. The training snacks must be virtually free of any carbohydrates or protein and must be small.  Good examples include:

• “Carbless cream soda”. Pour a few tablespoons of heavy whipping cream into a glass (check to make sure it has less than 1 gram carbs) over ice cubes and add sparkling water or herbal tea.
• “Platinum” tea or coffee. To an unsweetened cup of hot tea or coffee, add a tablespoon or two of heavy whipping cream or coconut oil.  The heavy cream has the advantage of easily blending with the tea or coffee, but some people find the coconut oil to be more energizing.  It comes as a solid but readily melts in the hot beverage; it tends leave some oily droplets on the surface because it does not emulsify as well as cream, but most people have no problem with that.  It is important not to add any sweeteners; even artificial sweeteners will tend to psychologically induce a conditioned preprandial insulin response (See Diet page).
• Macademia nuts.  These are high in fat with very few carbs.  Eat no more than a half dozen.
• A small piece of cheese. This is a great training snack, but keep it to one or two small slices of cheese.
• A tablespoon of oil. It may not sound very palatable, but a spoonful or two of extra light olive oil or other vegetable oil can be a great appetite suppressant and kick you into fat burning mode rather effortlessly. The oil works best if flavorless, or if you pinch your nose to avoid tasting it before rinsing.  This is the basis for the popular Shangri-La Diet of Seth Roberts. Roberts attributes the effect to breaking the connection between flavor and calories.  I propose an alternative explanation in my post on Flavor Control Diets.  and also in a long discussion thread on the Shangri-la Diet forum. In any case, flavorless or not, a small dose of oil is a very effective “bridge” to fasting.

4.  Savor flavored calorie-free beverages. To satisfy your need for flavor, enjoy herb teas and black coffee.  Decaf is preferable, but if you have a caffeine habit, go with it for now.  Don’t add any sugar or artificial sweeteners, since these can induce an insulin response that shuts down fat burning. Flavored beverages are a great boon to fasting because they satisfy the urge for flavor and provide some pleasure that can be a big help.

5.  Smell something aromatic while fasting. This is an old aromatherapy trick to turn off your appetite, but it has a scientific basis.  A strong aroma from herbs, spices, flowers or perfumes can rapidly dampen a craving by saturating the cephalic phase insulin response, as explained in my post on Flavor control diets — but you must not eat within 30 minutes after smelling. It is also useful to repeat the smelling frequently and cycle between very different aromas. This has been exploited in devices such as the SlimScents odor inhaler, but a few minutes with your spice rack, perfume bottles or flower garden may do the trick.  The good news is that the effect is long lasting and will permanently decondition your cravings.  Try it!

6.  Drink water frequently. This is an old standby and may seem boring compared to the above two suggestions.  But it works well in two ways: it tends to suppress hunger, and it keeps you hydrated. Keep in mind that the effect is often delayed, so wait 15-30 minutes after drinking the water before you pass judgement on it.

7.  Exercise briefly when hungry or tired. This is one of the more surprising ways to fight cravings, tiredness, mental fog, or borderline hypoglycemia. It may seem counterintuive to expend energy just at the point you are feeling hungry or tired. But it works incredibly well! The key is to do it at the first sign of a cranky or tired feeling, and you’ll head off it off at the pass.  By “exercise” I don’t necessarily mean going to the gym — unless you are used to that. Walking around for 5-15 minutes at a brisk pace is good enough, particularly if you can elevate your heart rate a bit. If you have been fasting, walking or other brief exercise will stimulate your liver to release glucose and free fatty acids, giving you an energy boost. It really is just about as good as eating a meal, for providing energy, and it has the benefit of providing a more sustained form of energy.  You’ll find that “after lunch” meetings are less soporific.

Getting out for a lunch time walk is an excellent alternative to eating lunch.  It gets you away from the kitchen or cafeteria, changes the scene and restores energy.   I probably eat only two lunches a week at work; the other days I go walking either outside or inside, depending on the weather.  Make it social and enlist a friend or start a small walking group – it is just as easy to converse while walking as while eating at a table.

When you get more experienced with fasting, the addition of extended, more intense exercise is very energizing and beneficial. With lower basal insulin levels and upregulated catabolic hormones and enzymes, you’ll find that a long run or workout with weights provides lasting energy and suppresses your appetite. Eating before or after the fast ruins the benefits. Wait at least several hours after the workout before breaking the fast. This may seem paradoxical, as it is virtually the opposite of what many experience who are not used to fasting.  But I have found it to be my experience.  For those interested in fasted workouts, checkout Martin Berkhan’s Leangains blog, as well as a recent article in Running Times on the benefits of glycogen-depleted exercise for greatly increasing your endurance; it appears to be a great strategy for learning to burn fat and weaning yourself off carb dependence,

A final word. The above approach, which emphasizes gradualism, should give your metabolism time to adapt.  For most people, this is enough to avoid any health issues with hypoglycemia or diabetic complications.  In fact, Lee Shurie cured his diabetes, normalized his blood sugar, and increased his energy level by carefully monitoring his blood glucose and gradually transitioning to intermittent fasting.  He found that all the traditional advice to eat low glycemic foods and exercise was insufficient to normal his blood glucose. Eventually, by delaying meal time and allowing his blood glucose to drop into the normal range, he found himself eating only at dinner time, and all the happier for it.  So transition to IF gradually. However, if you have any concerns, stop the fast and eat.  Consult with your physician if you have concerns.  Otherwise, check out the discussion of Intermittent fasting on the Getting Stronger Discussion Forum, to read others’ experiences.

Happy Thanksgiving!

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.

1. Flavor-calorie dissociation as advocated by Seth Roberts in his Shangri-La Diet
2. Sensory-specific satiety, as advocated in David Katz’s Flavor Point Diet
3. Tastants, another approach to sensory-specific satiety, as advertised in Alan Hirsch’s Sensa Weight-Loss Program.
4. Odor inhalers, a third approach based on sensory-specific satiety, as described in Alan Hirsch’s book Scentsational Weight Loss, and marketed by him as ”diet pens” offered by SlimScents

At first, some of these approaches appear to be mutually incompatible. The Shangri-La theory argues that strong or familiar flavors enhance appetite when they become associated with caloric foods.  The other three approaches, by contrast, claim that intense flavors or aromas suppress appetite, based upon the principle of “sensory-specific satiety”, whereby an increase in the intensity of a single flavor or odor induces satiety. However, on closer examination, all of the above theories are consistent with one another, as I will try to show. Furthermore, they each provide some useful clues about how to achieve a long term weight loss and relief from hunger cravings by paying attention to the role of flavor and other food cues.  Finally, as I will attempt to persuade you, only one of the above diets is truly a type of Deconditioning Diet that can lead to long term, permanent reduction in appetite, based on the principles of Hormetism.

This post is one of the longer, more complex ones I’ve written so far. It’s almost like a full chapter in a book.  For that, I apologize. But if you hang in there and try to follow the twists and turns in the science, I think at the end of this post you’ll find that certain puzzle pieces start to fit into place, leaving us with a framework that helps us to figure out some truly effective new methods of controlling appetite and weight. If  you want to skip to the punch line, you can find the simple explanation at the bottom of this post, below the dotted line, under the heading “A Unified Explanation of Flavor Control Diets” and “Lessons Learned”.  But for those who want to understand the science, read on….

I’d like to briefly review these weight loss programs and the underlying theoretical explanations for two reasons. First, I think that while the diets are useful, the explanations offered as to why they work are in several instances incorrect. I believe that the insulin response theory of appetite provides a more adequate explanation, and one which resolves the apparent contradiction between the two theories. Second, and more importantly, I think the insulin response theory of appetite, in combination with the philosophy of Hormetism, provides a scientific basis for the Deconditioning Diet.  As detailed on the Diet page of this website, the Deconditioning Diet is a weight loss program that offers the prospect of permanent and lasting changes to appetite and long term weight loss without dependence on consuming or using specific dietary agents or devices, such as is required by all four of the above flavor control weight loss methods.

The Shangri-La Diet. I credit Seth Roberts’ book by this name for first making me aware of the connection between flavor, appetite and weight control.  I tried the diet and it works.  I lost 10 pounds rather easily by using Roberts’ concept of flavorless calories to suppress appetite. Roberts discovered his diet while vacationing in France.  He tried some French sodas with “unfamiliar” flavors and found they suppressed his appetite almost totally. He found himself skipping meals or forgetting to eat, and he lost weight on the trip. He hypothesized that it was the unfamiliar flavors in combination with the calories from sugar that led to his appetite suppression. When he got home, he figured out that consuming sugar water with no added flavor would be as effective and simpler than using unfamiliar flavors.  Consuming daily fructose water left Roberts hungry enough to eat only “about one meal every two days”, and he steadily lost about 2 pounds a week, dropping from 185 to 150 pounds in short order. He satisfied his desire for non-caloric flavors by drinking tea and chewing gum, and his desire for texture by consuming  small portions of crunchy or chewy snacks like apples, nuts, or jerky.

Roberts then generalized his diet to stipulate ingesting small 200-calorie doses of flavorless calories, at least an hour before or after any meal.  “Flavorless” in this case means undetectable by the nose.  The sweetness of sugar appears not to count as a flavor, because it is detected only on the tongue and not by the nose.  (A test of whether something is a flavor is that it will become undetectable if you pinch your nose while tasting.  Sweetness, saltiness, and sourness are detected by the tongue only).  So besides sugars like sucrose and fructose, Roberts found that vegetable oils work well, particularly low flavor oils like extra light olive oil (ELOO) and certain nut oils.  On his website,  Roberts hosts a forum where an on-line community of SLD diet followers have extended the methodology to include variations such as “nose clipping” (wearing a nose clip or pinching your nose to suppress flavors while eating regular foods) or formulating various flavorless drinks and meals.  The SLD diet has clearly been successful for a great number of people,  many who have found it to be the least painless way to regain control of their eating and lose a large amount of weight, with great flexibility, no restrictions on the types of food you can eat, no calorie counting, and no sense of deprivation.

Roberts’ theory of weight control can be summarized as follows:  Foods with a weak flavor-calorie association will lower your body fat set point and cause you to lose weight; foods with a strong flavor-calorie association will do the opposite. He supports his theory of flavorless calories with evidence from the usually disparate fields of weight control (physiology) and associative learning (psychology). From weight control theory, he draws on the lipostatic theory of Gordon C. Kennedy.  Kennedy conducted experiments with rats in the 1950s which suggested that weight or body fat is homeostatically controlled to a relatively constant “set point”. When rats were fed less calorically dense food, they first lost weight, but then adjusted by eating more of the low-cal chow to re-establish their “set point”, just as a thermostat will turn on a heater whenever the temperature of the building drops below its set point. Kennedy’s experiments were backed up by similar studies in other animals and humans. In particular, Roberts cites a series of experiments by Dr. Michel Cabanac, a physiology professor at Laval University in Quebec. Cabanac worked with human subjects, who generally find glucose water pleasant to sip. Cabanac slowly pumped glucose water directly into the stomachs of his subjects, and then had them sip sugar water. For the subjects who had sugar injected into their stomachs, the sipped sugar water became less pleasant, and they felt full. In a follow up experiment, subjects first lost 8 pounds by just eating less of their usual diet, then the glucose injection experiment was repeated.  This time, the injected glucose water no longer reduced the pleasantness of the sipped sugar water, and the subjects remained very hungry. Roberts takes this to indicate that the increased appetite of this second group was caused by their actual weight being below their “set point” weight. In a further experiment, Cabanac found that letting subjects consume as much as they wanted of a restricted bland liquid diet let to significant weight loss without hunger.  And one of Cabanac’s students found even faster weight loss and appetite suppression by directly injecting the liquid nutrition through a stomach tube. This suggested to Roberts that flavors raise set point, and lack of flavor (as in direct injection of sugar or food to the stomach) reduces set point.

From associative learning, Roberts draws upon the very work of Pavlov that I have cited (for different reasons) on the Psychology page of this site.  He cites several experiments that appear to establish the general principle of flavor-calorie associative learning.  In one study with rats, Dr. Anthony Sclafini, a psychology professor at Brooklyn College in New York, allowed rats to drink water with two different flavors.  Whenever they sampled Flavor 1, a caloric starch compound (Polycose) was injected into their stomachs, but when they drank Flavor 2, plain water was injected into their stomachs.  The rats developed a strong preference for Flavor 1, and this preference persisted several days even after the injections were stopped.  Since they could not “taste” the injected Polycose, Sclafini and Roberts take this to provide flavor-calorie associative learning.

Putting these two lines of research together, Roberts concludes that consuming calories with familiar or strong flavors tends strengthen flavor-calorie association and preference for those flavors, and will raise the weight set point, whereas consuming flavorless calories or calories with unfamiliar flavors tends to reduce both the flavor preference and the set point.  Roberts and his followers have used the hypothesized connection between flavor-calorie association and body fat set point to make predictions and extend the diet. For example, Roberts predicted and confirmed that appetite suppression and weight loss can also be achieved by consuming foods with unfamiliar flavors, so one variation of SLD is to add “crazy spices” to foods to break the flavor-calorie association, or by using nose-clipping to suppress detection of flavors while eating.

However, the success of the SLD diet in itself does not prove that Roberts’ explanation for why it works is correct. I believe that Roberts explanation is incorrect for several reasons:  (1) the set point theory is not empirically testable;  (2) Roberts learning theory is based on a misunderstanding of Pavlov’s theory of associative learning; (3) Roberts’ learning theory makes several false predictions and fails to explain other facts about weight loss; (4) there is an alternative explanation for why SLD works that can better explain these other facts about weight loss.  I’ll take up these criticisms in order.

Lipostatic set point theory of weight control. According to Roberts, if you weigh less than your set point, “you will be hungry and think about food” and the bigger the gap, “the more you will think about food, and the more food it will take to feel full when you eat.  It is nearly impossible to weigh much less than your set point for a long time–the hunger becomes unbearable.”  (SLD, p.9) Similarly, if you weigh more than your set point you will not be hungry and “When you eat, you will feel full rapidly.” It is apparently not your weight, but your body fat content, that is compared with a set point. “When your body-weight regulatory system detects that you have less fat on your body than your set point, it makes you more hungry than usual between meals and increases how much food you need to eat to feel full.” (SLD, pp. 41-2)

And yet the lipostatic set point does not seem to operate like temperature set point on a thermostat. Whenever the temperature is below the thermostat set point, the heater turns on immediately, or after a short delay. And whenever the temperature is above the set point, the heater never turns on–until temperature drops on its own, or with the assistance of air conditioning. But this is not the case with body weight “set point”. When you weigh 8 pounds less than your set point, you don’t eat continuously in one session until the set point is reached. Likewise if you weigh 8 pounds more than your set point, you don’t totally stop eating until your weight drops to the set point level. Instead, most people have a certain rhythmic frequency of eating alternating with not eating. Something else regulates this rhythm of meals even when we far from set point. (As I’ll suggest below, that “something” is the hormone insulin).

Roberts acknowledges that set point is not fixed, and he posits that your set point is directly influenced by what you eat. He explains that between meals, your set point goes down gradually, and the higher your set point, the faster it goes down. But, according to Roberts, your weight goes down faster than your set point, which is “why not eating causes hunger–and why diets that deprive you of food don’t work.” Eating foods with flavor-calorie association will immediately raise set point; and the stronger the association, the greater the increase in set point.

But this is an odd sort of set point that is never really set! The very thing that is controlled by set point (eating) itself causes the set point to change. It is as if a thermostat setting were itself influenced by the temperature in the house, rather than by the intentional decision of the house occupants. The set point concept starts look very flexible, with a lot of external influences and circular feedback loops. (It reminds me of how epicycles were added to the Ptolemy’s geocentric theory of the solar system in order to explain the apparent zigzagging of observed orbits of plants and stars around the earth, until Copernicus eventually came up with the simpler heliocentric theory in the 16th century). If set point is always changing, how could you verify this? It just seems like a convenient theoretical entity that can never be proven or disproven. Roberts’ claim that highly flavored caloric foods cause weight gain because they are “high set point foods” is an example of this circular reasoning.

There is also one other weird aspect of the lipostatic theory of weight control.  It seems to commit us to the view that each of us has a “natural” set point weight or fat mass, which we cannot change.  Unless, that is, we following the Shangri-La Diet and we commit ourselves to eating bland foods, at least periodically–forever. If we are born with a “fat” set point weight and eat flavorful caloric foods, we are destined to get fat. Naturally thin people who can eat flavorful foods are just lucky, because…they are born with a low set point.  Somehow, I doubt this.

This does not mean we should throw out the concept of a set point.  We just have to pick a physiologically verifiable set point.  True examples of set points and homeostasis are blood pH and body temperature which are controlled in a narrow range, under normal circumstances. There is not anything that you can do to alter these set points, and nor would you want to do so. Fevers, hypothermia, and ketoacidosis are indicators of disturbance or pathology, and the organism works hard to restore temperature or pH to the healthy set point values in such cases. Furthermore, the physiological basis of these homeostatic mechanisms for regulating body temperature and blood pH are well known. So I think that extending the set point concept to such a variable quantity as body weight is neither legitimate nor useful, and there burden of proof should be on its advocates to demonstrate an empirical basis for it.

Roberts does acknowledge physiology when he claims that set point is related to the concentration of leptin in the in the bloodstream:

In order to regulate the amount of body fat, the brain must be able to know how much body fat you have, just as a thermostat needs a built-in thermometer to keep track of the room temperature. Leptin serves as the brain’s body-fat thermometer: The concentration of leptin in your blood tells your brain how much fat is in your body. Leptin is produced by fat cells. When your body fat goes up, so does the amount of leptin in your blood.  When your body fat goes down, leptin goes down.  (SLD, p. 143)

This is getting closer to a bona fide physiological explanation. In fact, I agree that hormones drive weight control, I just think that Roberts has chosen the wrong hormone. There are two problems with choosing leptin. First, while leptin does play a key role in signalling satiety to the brain, it is not the whole story. First, the leptin signal does not always work. People can become resistant to leptin.  The brain can’t always “hear” leptin even when it is elevated, leading people to overeat. This is especially true with obese individuals.  The leptin signal can also be blocked by ingesting a meal high in carbohydrates, since carbohydrates lead to high triglyceride levels in the bloodstream, and this can block the leptin signal, again leading to overeating. Furthermore, leptin is not the only player in hunger signaling. The brain integrates the signal from leptin with that of other appetite signallers, including hormones such as ghrelin, and neurotransmitters such as neuropeptide Y, serotonin, dopamine and various opioids.  We need to look further up the stream to the root cause of hunger, not the “messengers”.

Another problem with the leptin theory is that is inconsistent with at least two observational facts:

1. The observed variability in body weights in the population. Leptin is known to increase in fat individuals and decrease in lean individuals.  So lean individuals, who have lower levels of leptin, should be hungry and want to eat more, until their leptin reaches a “satiating” level.  However, that would seem to rule out the existence of lean people. Everyone should eat until their leptin level reaches the “normal” level.  And yet that is absurd, because most lean people are not ravenously hungry.  That implies that every individual can have a different “normal” leptin level.  That is in fact the case, but then it removes leptin as a homeostatic regulator of weight or body fat.
2. The suppression of hunger observed during extended fasting. After an initial period of cravings, light-headedness or other hypoglycemic response, people who are fasting for extended periods of 12-24 hours or longer commonly report appetite suppression and a surge of energy.  This cannot be explained by the lipostatic set point theory or Roberts version of it. To repeat what I wrote above, according to Roberts, your weight goes down faster than your set point, which is “why not eating causes hunger–and why diets that deprive you of food don’t work.” But if weight is dropping faster than set point during fasting, your hunger should increase monotonically, that is, it should get steadily more intense, without dissipating.  Yet that is not what happens.  After a period of adjustment, as insulin drops, glucagon rises along with adipose tissue lipase, and adipose tissue begins releasing free fatty acids into the bloodstream, while the liver breaks down glycogen into glucose and proteins into glucose via gluconeogenesis.  So a constant level of glucose in the bloodstream is restored, and there is no sense of deprivation or “unbearable” hunger.  Most people who fast, including myself, find it quite pleasant.  I think the bad rap on fasting comes from people who have not studied the physiology of fasting and either haven’t tried it, or haven’t given their bodies enough time to adapt.

The glucostatic theory. There is a much better alternative to the lipostatic theory of hunger and weight regulation:  namely, the glucostatic theory of Jean Mayer, as it has been developed into a fuller theory of the homeostatic regulation of blood glucose by the hormone insulin. While there are many hunger signaling compounds, ultimately these signals are either responding to or predicting what is happening or likely to happen to blood glucose concentrations. In the glucostatic theory, there is also a set point that controls hunger, and it is blood glucose concentration. According to the glucostatic hypothesis, there is no body fat “set point” that our body attempts to defend, no “natural” level of fatness or leanness. This is evidenced by the fact that it is possible to gain or lose a lot of weight and main these changes. Whether we are fat or lean, our body strives to maintain glucose concentration within a physiologically tolerable range of about 70 to 150 mg/dL. Below that level, hypoglycemia sets off hunger pains, headaches and–in extreme cases–shock and coma. Above that level, there can be both acute problems with high blood glucose and chronic problems with elevated blood glucose, leading eventually to hyperinsulinemia and diabetes. There is an excellent discussion of the glucostatic and lipostatic theories of weight control in Chapter 24 of Gary Taubes’ Good Calories, Bad Calories, delineating further problems the lipostatic theory.

This is not to say that weight is not remarkably stable in most people for long periods of time. But this stability is not the result of homeostatic control.  Rather than being a “set point”, body fat may be a “settling point”.  Taubes is very articulate on this point:

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.

This is where physiological psychologists provided a viable alternative hypothesis to explain both hunger and weight regulation. In effect, they rediscovered the science of how fat metabolism is regulated, but did it from an entirely different perspective, and followed the implications through to the sensations of hunger and satiety. Their hypothesis explained the relative stability of body weight, which has always been one of the outstanding paradoxes in the study of weight regulation, and even why body weight would be expected to move upward with age, or even move upward on average in a population, as the obesity epidemic suggests has been the case lately. (GCBC, pp. 428-9)

In effect, the apparent stability of weight results from a relative constancy in many factors–hormone activation, food intake, physical activity–any change in which can shift this balance to a new stability point.

The glucostatic theory also provides explain how appetite can change on a minute-by-minute basis. Typically, a drop in blood sugar is associated with hunger and the initiation of eating.  While blood sugar can drift down on its own, the more usual scenario is that food cues such as aromas, or the time of day, lead  to a psychologically triggered secretion of insulin are the immediate causes of a dip in blood sugar, with its attendant hunger signals.  This usually occurs at meal times because of prior conditioning.  Blood sugar can also drop when the body is running low on glycogen and is having difficulty switching over to fat or ketones, or when blood sugar is depleted by exercise or other activity that outstrips the ability to resupply glucose from the tissues.

Unlike blood glucose and insulin–which can change by the minute and correlate well with the well known rhythms of appetite and satiety–body fat and body weight change much more slowly, and therefore do not seem to be good candidates for direct control, as required by the set point theory of weight regulation.

Associative learning. There is a second problem with Roberts’ explanation of why the Shangri-La Diet works. One of Roberts central claims is that body fat set point is influenced by flavor-calorie association, and that the strength of the association between flavor and calories comes about by means of associative learning. In this regard, Roberts explicitly invokes Pavlov to explain why the the SLD requires that flavor and calories be detected at separate times:

In Pavlov’s experiments, the bell was the signal and the food was the outcome.  The food was given at the same time the bell was turned off.  Had the food been given many minutes after the bell was turned off, the dog would not have associated them  at all. (SLD, p. 47)

Roberts further supports this contention about timing by citing experiments with rats indicating that “a flavor-calorie association was learned even when there was a thirty-minute gap between eating the flavor source and eating the calorie source” (p. 70), but a one-hour gap was sufficient to prevent such a learned association from forming. The flavorless calorie window of one hour stipulated for the SLD is based on the Pavlovian principle that “the more delayed the outcome, the weaker the association”.

But I believe Roberts’ interpretations and conclusions regarding Pavlov’s finding are not correct here. First, Pavlov did in fact show in his experiments with dogs that a delay between a stimulus such as a buzzer, and a delayed feeding would merely reinforce a delay in the salivation. The dogs would wait the required amount of time:

As his technique became more practiced, Pavlov’s laboratory began investigating the canine sense of time. After a dog was trained to salivate at a flash of light, the delivery of the stimulus was postponed by three minutes. Before long, the dog learned to anticipate the delay. Three minutes after the signal, the animal’s mouth would water. (The Ten Most Beautiful Experiments, p. 132).

But second, note that Roberts in the previous quote is talking about an association between the bell and the food presentation (two stimuli). That is indeed associative learning, because both the bell and the food can be perceived. The bell and food repeatedly occur together, and become psychologically associated.  This association is strengthen considerably by reinforcement.  The bell is a conditioned stimulus (CS) and the food is an unconditioned stimulus (US) and classical conditioning is all about associating CS with US, by virtue of reinforcing the unconditioned response (UR). In this case the UR is salivation and an increase in appetite, and the reinforcement is the rise in the dog’s blood sugar that occurs after it eats the food. (If the food was taken away before being eaten, there would be no reinforcement).

Yet in his explanation of why the Shangri-La diet works, Roberts talks about an “association” between flavor and calories. However it is a misapplication of the concept of associative learning to speak of “associating” a perceivable entity (flavor) with an unperceivable physiological reaction (detection of “calories”). The calories cannot be directly perceived by the sensory apparatus. Rather, the ingestion of food results in a physiological response, a rise in blood sugar, and its further consequence, secretion of insulin. There is a perceivable consequence of the calories (hunger), which is possible to associated with certain stimuli.  But that is not what Roberts is claiming. He says that we learn to associate flavors with calories, not with hunger or satiety. The relationship between a perceivable stimulus and a physiological response, if reinforced, gives rise to classical conditioning.  This is distinct from associative learning, in which two perceivable stimuli become associated with each other when they occur together repeatedly.

Put another way: it is not strictly correct to say that people “learn” to make “associations” between flavors and calories, especially since they are not directly aware of the calories (other than by reading food labels). All we can discern is whether or not the flavorful food provides relief from hunger. Roberts sometimes seems to conflate awareness of calories–a requirement for associative learning–with physiological detection of calories. But physiological “detection” by the digestive system is not associative learning.Strictly speaking, it is not a flavor-calorie association, but rather an association between flavor and the satisfaction of appetite. An even better way is to formulate this as a stimulus-response relationship, since the primary response is physiological and not conscious. In this case direct response to the stimulus of flavor is insulin secretion, and indirect responses are blood sugar and appetite.  Pavlov primarily studied the conditioning of stimulus-response relationships; the associative learning was merely an explanation for how a secondary, conditioned stimulus could become secondarily associated with the primary unconditioned stimulus.

Even if we were to accept Roberts position that unconscious detection of caloric foods by the digestive system is sufficient for calories to play a role in “associative learning”, we are left without an explanation of how calories per se can be detected.  In this regard, the digestive system does not recognize all “calories” as a monolithic unit of food, as Roberts seems to suggest.  His explanation of how low carb and “good carb” diets work overlooks significant differences in how calories in different types of macronutrients interact with the digestive system. He seems to assume the only difference between carbohydrates, proteins and fats is how quickly they are released and detected:

When a food is digested more slowly, the calories in that food are detected more slowly. Thus there is more of a gap between the signal (flavor) and the outcome (calories). I believe this is why low-carb and good-carb diets work: They replace foods  that are digested quickly, such as bread, with foods that are digested slowly, such as vegetables. The foods that are digested more slowly have weaker flavor-calorie associations. They raise your set point less.  (SLD, p. 47)

But this does not seem very plausible.  Low molecular weight oils can be digested and absorbed as least as quickly as most starches. The reason that oils lead to better appetite suppression and weight loss than simple carbs is not that they are detected more slowly, but rather than they induce little or no insulin response. Furthermore, fats will result in increased appetite in weight if they are combined with even a modest amount of carbohydrates, because the insulin response will cause them to become “fixed” with the glucose to form triglycerides in the adipose tissue. It is critically important to consider the types of macronutrients and how the endocrine and digestive system responds to them alone and in combination.

A better explanation for Robert’s one-hour rule is based on the dynamics of insulin secretion, and the way that this can become conditionally mediated via sensory stimulation of the vagus nerve . When correctly understood in terms of insulin response, the one hour rule should be changed to an asymmetric rule.  In fact, one should only need to wait about 15-30 minutes after ingesting non-caloric flavors before consuming calories, but depending on the meal size, one may need to wait an hour or more before consuming flavors after eating.  This is because the pre-prandial insulin response is shorter and smaller than the post-prandial insulin response.

In fact the one-hour rule must be differentiated even further, based on the macronutrient composition of the calories, and it leads to a number of predictions that diverge from the SLD:

1. Wait at least 15-30 minutes after a flavor or aroma before ingesting carbohydrate containing foods. (This is to allow the pre-prandial insulin response to subside, and blood sugar to renormalize).
2. Wait at least an hour after consuming flavorless carbohydrate-containing foods before ingesting flavors. (This is because the post-prandial insulin is much larger and takes longer to return to baseline than the transient flavor-induced pre-prandial insulin response).
3. The same rules apply to meals which contain large amounts of protein.  Protein is much less insulinogenic that carbohydrates, but large protein meals and certain types of protein are insulinogenic.
4. You can eat fats and flavors together without any worry, because fat is not insulinogenic alone–it requires the presence of a little carbohydrate or a lot of protein to be removed from the bloodstream by insulin.

The flavor-insulin response, which is mediated by the tractus solitarus in the brain and the vagus nerve, is a conditioned response.  It will be strengthened whenever the flavor cue is concurrent or closely followed by a the ingestion of insulinogenic foods, foods which in themselves produce an insulin response when detected by the glucose receptors in the stomach and intestines. Essentially, the flavor-insulin response is a predictive response that readies the digestive tract for food that is coming, by making the food more absorbable. Secreting pre-prandial insulin for a pure fat meal or a small protein meal has no value, and that conditioned response will tend to extinguish. So that leads to another set of predictions. In particular, despite what Roberts claims, fats and sugars should work very differently in the SLD. So here are some predictions made by the insulin-regulated glucostatic theory of hunger, all of which are either not predicted by SLD or are diametrically opposed to what SLD would predict:

1. Consuming pure fats like olive oil or heavy cream should suppress appetite even if they are flavored. This only works, however, if no more than a trace of carbohydrates or proteins.  (This works because fats are noninsulinogenic).
2. Increasing the dose size of oils even to large doses should increase appetite suppression
3. Increasing the dose size of sucrose or glucose beyond the minimum dose, should reduce appetite suppression.  A small amount of sucrose or glucose increases satiety because it raises blood sugar slightly, and flies “under the insulin radar”.  Insulin is not secreted until blood sugar rises above a certain threshold, typically 120 mg/dL or so.  But once it exceeds that threshold, insulin kicks in, and blood sugar drops.
4. Sipping sucrose or glucose slowly will maintain appetite suppression.  If this is done slowly enough, the addition to blood sugar just balances out the amount of blood sugar consumed to meet metabolic needs.  But this is a careful balance.
5. Increasing the dose of fructose, xylitol, erythritol, or other non-insulinogenic sugars should suppress appetite at any dose.

Prediction 4 is consistent with SLD. Predictions 2 and 5 are consistent with SLD, but not predictable from it. Predictions 1 and 3 are contrary to the fundamental assumptions of SLD, and would not be predicted by it.

For anyone who is interested in subjecting SLD to a test, I would be interested in their experience in attempting to verify or refute the above predictions, especially 1, 2 and 3.

The Flavor Point Diet. (FPD). This diet, created by David Katz, is based on the concept of “sensory specific satiety”. Eating a meal with flavors in multiple “competing” categories such as sweet, salty, or savory, somehow stimulates the “appetite center” of your brain, causing overeating. Limiting the flavor categories in a meal or snack to one or two flavor types makes it easier–more rapidly and with less food– for your brain and stomach to reach the “flavor point”, a state of satiety that causes you to stop eating, with less food. This concept is reflected in the popular notion of “multiple stomachs”, whereby you can feel stuffed after eating one course of a meal, but you often seem to find additional appetite for dessert or something different.  The FPD advises you to restrict the number of simultaneous flavors within a meal, but overcomes the potential boredom by allowing you to eat a variety of flavors over the course of a day or week–just not “excessive variety” all at one time.

Katz bases most of his case for sensory specific satiety on the way in which flavors stimulate the production of neurochemicals that activate the hypothalamus:

As soon as you taste food, the sensory information registers in the hypothalamus in the brain, which, depending on the flavor of the food, sends out signals to eat more or less.  Because of this sensory relay system, the appetite center in your hypothalamus can become aroused–and in some cases overly aroused–by how a food tastes. (FPD, p. 4)

As soon as you bite into any food, sensory stimulation of nerve endings on the tongue leads to the release of a number of chemicals, including opioids, into the bloodstream.  You release more opioids–the body’s natural version of drugs like morphine–when you consume foods high in sugar and fat, creating a powerful, neurochemical drive to overeat those foods.  These opioids and other chemicals enter the bloodstream and carry their messages to the hypothalamus, which sends out yet another set of chemicals to regulate appetite. The more flavors your taste buds register, the more stimulated the hypothalamus becomes, releasing the hunger-promoting neuropeptide Y. When you taste a lot of flavors at once, the brain releases a lot of neuropeptide Y.  Meanwhile, in response to the smell and taste of food, your stomach produces the hormone ghrelin, which also stimulates appetite.  It continues to produce this hormone until you eat enough food to literally fill your stomach and stretch the stomach wall. Farther down the line, in your intestines, levels of several hormones rise to varying degrees–depending on the nature of your meal–either inducing more hunger or turning off hunger. (FPD, p. 4-5)

Katz claims that by “organizing” the flavors in our diet, we can manipulate this chain of chemical and  signals and “subdue the appetite center in your brain sooner, before you’ve overeaten.” (p. 9) Katz also does acknowledge a role for insulin in controlling blood sugar, and points out that fast carbs cause a rapid blood sugar surge and an insulin spike which tends to overshoot and lead to a drop in blood sugar, whereas low glycemic carbs like oatmeal result in a lower rise in blood sugar, a slower release of insulin, “no rapid surge and dip in blood sugar levels” and sustained satiety.  But he does not make any direct connection between flavor and the insulin response, putting the onus on the neurochemical triggers like opioids, neuropeptide Y, and ghrelin.

The FPD establishes how flavors can begin a cascade that induces appetite. Katz is probably correct that the effects of individual flavors have a saturating effect on this response, and that the response can be increased by combining multiple flavors. I think that Katz overstates the role that neurotransmitters and leptin play in hunger and appetite.  Neurotransmitters and leptin are are important as primarily signaling compounds to the brain, but they are not the primary causal agent in that chain. Insulin is much more directly involved in the control of appetite, because it is insulin that reduces blood sugar to physiologically unsustainable levels in the first place, and the signaling compounds are merely the messengers. Blaming these signalling compounds for hunger is like blaming a witness for the crime. Perhaps neuropeptides and leptin can signal hunger without concurrent insulin response. I think this is unlikely, but if it occurs, I suspect it is because these signals have independently become classically conditioned to respond to flavors and other food cues that have become associated with the presence of food. As with insulin, these neurotransmitter responses to sensory stimuli can be deconditioned upon experience. However, Katz treats the neurochemical responses to flavors as “hardwired”, overlooking the fact that they are learned or conditioned responses.  The responses will strengthen if reinforced by eating food that increases blood sugar, and will weaken if not reinforced. His claim that sugar and fat alone cause the release of opioids into the bloodstream is not documented and seems unlikely. The tongue does not detect sugar and fat directly. In fact, some neurological research by Woolley et al at UCSF indicates that it is flavors, and not the macronutrient content of foods, that stimulate opioid secretion by the nucleus accumbens in the brain. To the extent that the hypothalamus is engaged, it requires a detectable signal such as flavor.  As Teff showed (see Diet page), the tractus solitarus will trigger the vagus nerve to secrete insulin only in response to flavor and scents that it has learned and expects to be associated with blood-sugar raising foods.

Sensa tastants.  Closely related to the Flavor Point diet is the use of tastants as Alan Hirsch has developed for his Sensa Weight Loss Program.  The Sensa tastants are intense non-caloric flavors that are sprinkled on foods to enhance flavor intensity.  The tastants are matched the flavor class of the foods: savory tastants are sprinkled on savory foods, while sweet tastants are sprinkled on sweet foods. The principle of sensory-specific satiety is identical with that of the Flavor Point diet. One is still advised to eat only one or two “flavor categories” of food at a meal. The advantage of Sensa over FPD, perhaps, is that the satiating “flavor point” is reached earlier in a meal, with less food and fewer calories consumed than otherwise.  It seems to me the the same result could be achieved by spicing your savory foods and adding non-caloric sweeteners to your desserts.

As with FLP, however, tastants will do nothing to fundamentally alter or extinguish strong flavor-insulin responses. So one remains vulnerable to a strong appetite returning when combining foods, and has to observe the principle of limiting the number and variety of flavors at any given meal.

The bottom line, with both FLP and Sensa, is that by confining yourself or intensifying a single flavor, you allow the insulin response to that specific flavor to saturate earlier, thereby limiting the appetite-inducing property of insulin.  If you were to add more successive different flavors, you will tend to stimulate separate flavor-detection pathways and add another wave of insulin secretion and stoking of appetite.

Odor inhalers (Scentsational Weight Loss). Direct exposure to saturating levels of food aromas is yet another way to exploit the sensory specific satiety mechanism. Even though it exploits the same mechanism, it is in an entirely different class and–as I will argue–odor inhalers have the potential to engender long term appetite deconditioning and weight loss.

Alan Hirsch describes his discovery of this phenomenon in his book Sensational Weight Loss (SWL), and the same concept is exploited in the commercial “diet pens” sold by SlimScents. There are a number of other related pens and inhalers marketed as “aromatherapy”. Hirsch reports a remarkable conclusion from his six month study of the use aroma devices for to quell appetite and spur weight loss. The study included 3193 participants, 86% of whom were women, and most of whom were significantly overweight (average weight = 217 lb.). Participants were given small odor inhalers, similar to lipstick dispensers, containing pleasant smelling substances. Three aromas were used: green apple, peppermint, and banana. Hirsch found that varying the aromas was more effective than sticking with the same aroma. Participants were asked to open and sniff the aromas whenever they got hungry–three sniffs in each nostril. But otherwise there were no forbidden foods or other dietary restrictions. The results were impressive. The average weight loss was 5 pounds per month.  Some people lost more than 100 pounds over the six month study. What is especially interesting to me, however, is that there was a permanent deconditioning effect, along the lines of the Deconditioning Diet (see Diet page).  Here are Hirsch’s comments regarding “deprogramming” of the participants’ learned responses to flavors, leading to long-term changes in eating habits:

Just as we have learned to respond to the smell of certain foods by feeling hungry and wanting to eat, we can, in a very real sense, “unlearn” or deprogram ourselves. For many people the smell of any food triggered hunger. Smell a doughnut, salivate; smell a pizza, and the stomach growls. Actually, most of us experience this much of the time; but in the overweight person, this conditioned, or learned, response can be quite. powerful. It’s exciting to realize that people can recondition themselves to smell an odor and not respond with hunger. In the absence of a food associated with the smell, hunger disappeared, the desire to eat subsided, and a pattern was broken. In many cases, this was a long-standing pattern that was broken during the six month study. (SWLP, p. 33-4)

Further evidence of a long term change was reflected in the frequency of use of the odor  devices during the study. At the beginning of the study, participants reported needing to sniff 200 times a day or more; by the end of the study, only occasional sniffing was needed to keep appetite in check. So the the aroma devices don’t themselves become habit forming–the dependence actually decreases over time as new eating habits are consolidated.

In Chapter 4 of Scentsational Weight Loss, Hirsch provides some additional advice, namely that we pre-saturate our satiey centers by sniffing our meals before the first bite to letter the odor molecules fully stimulate the olfactory bulb.  He recommends that we slowly chew and savor the flavor of each bite in order to “fool” the hypothalamus into “believing that more food has been ingested than is actually the case. He also recommends eating food warm or hot to maximize the aroma, adding spices whenever possible, and choosing the more strongly flavored versions of foods.  ”For example, if you eat popcorn, eat the cheese-flavored varierty, or choose an onion bagel over a plain one.” (SWLP, p. 62).

On the face of it, this advice is diametrically opposed to that of Seth Roberts’ Shangri-La Diet!  Roberts argues that blander foods induce weight loss, whereas Hirsch is arging for more intensely flavored and spiced foods. Who is right and what gives?

Here is where all three diets — SLD, FPD, Sensa, and SWL– come together.  After promoting the enhancement of flavor, Hirsch adds:

Try limiting your food choices at any one meal. We still encourage variety, but not necessarily all at one time. We have found that people who want to lose weight should eat only two or three different foods during a meal rather than eating a little bit of many foods…Avoid buffet tables and “all you an eat” food bars. Even salad bars can be dangerous…Even with a smell device, too many selections and unlimited choices spell potential overeating. (Sensa Weight Loss Program, p. 63-64)

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A Unified Explanation of Flavor Control Diets. Here is my summary explanation that can account for the observed effects of all four dietary approaches:  Familiar flavors can induce a pre-prandial insulin response which leads to increased appetite and weight gain. This preprandial insulin response saturates separately for each basic flavor type (savory, salty, sweet, etc.). This saturating pre-prandial insulin response is is a learned response, and one that is reinforced only if it results ultimately in a rise in blood sugar and psychological satiation. If that flavor or aroma is not followed by more eating, it will eventually diminish or extinguish as a cue.

Here then is how this explains each of the four flavor control diets:

1. SLD explanation. Eating foods that contain carbohydrates (and to a lesser extent, proteins) with strong, familiar flavors will lead to a rapid pre-prandial insulin response which may be enough to cause a dip in blood sugar, stoking hunger and leading to further eating. Eating a small amount of bland or flavorless carbohydrate will satisfy hunger by slightly raising blood sugar, and will induce only a small post-prandial insulin response, insufficient to cause a rapid decline in blood sugar, so appetite will remain suppressed.  While SLD keeps insulin in check, it does so only so long as flavor cues are not present. But SLD does nothing to weaken the connection between familiar flavors stimuli and their insulin response, it merely eliminates the stimuli.  One would expect appetite to return when the familiar flavors are re-introduced.
2. FPD explanation. Eating foods with familiar flavors will induce two insulin responses:  a small pre-prandial response and a larger post-prandial response.  However, the pre-prandial insulin responses for that flavor peaks within about 4 minutes after exposure, and sensory detection of that flavor will rapidly saturate.  After it saturates, any further exposure to that specific aroma (or aroma class) will not induce any further insulin response for an extended period of time — up to about an hour. However, introducing new flavors, aromas or other food cues will cause additional secretion of insulin, increasing appetite. The more intense the flavor or aroma, the faster the saturation.
3. Sensa explanation.  The explanation for Sensa is the same as that for the FPD.  Activation of a sensory response to a flavor will induce a small and rapid pre-prandial insulin response. For a single flavor or aroma class, the detection of that flavor will saturate after a certain amount of time, after which it will not prompt any further insulin response.  If multiple aromas are sniffed, then all those smell receptors will become saturated, after which any further pre-prandial insulin response will become muted. Since the Sensa tastants contain no or minimal calories, they provide a way to reach flavor saturation faster, with fewer calories.  In that way, the use of tastants is more effective than the Flavor Point Diet, since fewer net calories are consumed while satisfying one’s appetite.
4. SWL (odor inhalants) explanation. With sensory-specific satiety approahes like FPD and Sensa, the stimulus-response relationship between flavor and pre-prandial insulin response is reinforced. The stimulus may saturate, but the connection with the insulin response remains in place, so that at subsequent meals, the flavor will induce pre-prandial insulin.  However, with SWL, the relationship between flavor and pre-prandial insulin is not reinforced, so it extinguishes!  This is a crucial difference. For this reason, SWL is actually a deconditioning diet that results in long term changes in the flavor-insulin response that suppress appetite and lead to weight loss.  Eventually, the aroma inhalers are no longer needed, or only rarely, to maintain the “deprogramming” that Hirsch alludes to.  By contrast, SLD, FLP and Sensa are not deconditioning diets, but merely methods of suppressing or limiting appetite that work by either minimizing or saturating the stimulus of food cues, but doing nothing to weaken the flavor-insulin response.

Lessons learned. Where does this leave us?  There is a lot to be learned from all four flavor control diets. Flavors and aromas that become associated with foods, particularly carbohydrate-containing foods, strengthen the insulin-response to those flavors and aromas, increase appetite, and tend to increase the consumption of those foods, leading to weight gain. This insulin response and the resulting appetite can be significantly dampened by limiting the variety of flavors while eating.  However, a much larger benefit is possible by using flavors to decondition your appetite:

• You can expose yourself to flavors without carbohydrates or other insulinogenic foods and this will dampen the flavor-insulin response, and lead to a decrease in appetite that is induced by food cues.
• By exposing yourself to a variety of flavors or aromatic stimuli without eating, you will saturate a fuller range of satiety centers and even more effectively block an insulin response.  Sniffing a variety of aromas of different types–savory and sweet– without eating can be helpful in curbing appetite.

These findings have been incorporated into the second phase of the Deconditioning Diet, as described on the Diet page in this website.

Please leave a comment.  You can also check out (and maybe start) a discussion on the Diet Forum linked to this blog.