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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

…

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

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

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

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

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

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

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

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

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

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

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

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

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

That theory has been around the block but it is in fashion again.   In 2009, David Kessler’s book, “The End of Overeating” put forward the thesis that food in contemporary American food has been deliberately engineered–by adding fat, sugar and salt–to exploit our neurochemistry and hijack our free will.

More recently, one of the luminaries of the Paleo movement, Stephan Guyenet, has formulated his own version of this theory, in a compelling series on his Whole Health Source blog, arguing that  ”food reward” is a main driver of obesity. His prescription:  eat a bland diet. Guyenet’s talk about this at the Ancestral Health Symposium last month is the buzz of the paleosphere.

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

Brain chemistry. Stephan Guyenet’s series on food reward, like Kessler’s book, pins the blame for obesity largely on the increased availability of more palatable “high reward” food.

According to USDA data, Americans today eat an astonishing 425 more calories per day than they did in 1970.  That is the reason for the obesity epidemic, plain and simple.  However, that fact doesn’t tell us why we’re eating more calories, so its usefulness is limited. The increase in calorie intake has come primarily from refined carbohydrate, but even that doesn’t get us very far, because why did we decide to eat more refined carbohydrate?  Probably because of the systematic efforts of commercial food manufacturers to increase the palatability/reward value and availability of processed food.  In the last four decades, the US has become saturated with hyperpalatable/rewarding commercial and restaurant foods including fast food, soda, french fries, chips, candy and other industrial products.  I’ve seen people claim that they ate these things just as much in the 1960s and 70s, but the USDA and National Restaurant Association data show otherwise.  The qualitative changes in the US diet have been swift and profound… (A Roadmap to Obesity, August 25, 2011)

But what is it about food that makes it rewarding or not?  Guyenet suggests that food reward relates to opioid and dopamine signaling:

Feeling satisfied after eating something is not reward. If you keep eating a starch food beyond what’s appropriate, that is probably because it has too much reward/hedonic value for you. Opioid signaling, implicated in hedonic processing, shuts off satiation signals in the brain and may also increase the setpoint. Dopamine signaling, implicated in reward, can strongly influence food intake and also seems to be able to increase the set point.

In “The End of Overeating”, Kessler also emphasizes the way that “hyperpalatable” foods stimulate dopamine, opioids and other reward neurotransmitters.  To be fair, both Guyenet and Kessler acknowledge that food reward is not the only explanation for obesity.  They acknowledge the role of genetics, exercise and other factors.  But for both of them too-tasty food is the leading culprit.

The relativity of taste.  But is it really that simple?  Are some foods inherently and invariably rewarding? Do our taste buds and noses directly respond to tasty foods or foods high in fat, sugar or salt by stimulating the secretion of dopamine and opioids in the brain, turning us into addicts? Somehow, it must be more complex than that.

Seth Roberts has postulated a different explanation, in which learning plays a role. His Shangri-La Diet was derived from observations that tasty foods lead to weight gain only after repeatedly encountering the flavor and the calories together. Roberts calls this process “flavor-calorie association”.  It’s a Pavlovian conditioning process: the more habitual the association, the greater the obesogenic potential of the food or beverage.  So his diet involves regular doses of “flavorless calories” in the form of bland oils, sugars or proteins.  Alternative strategies include consuming foods with unfamiliar flavors or “crazy spices”, or flavored noncaloric beverages like herb teas. (For more on flavor-calorie association, see my post on Flavor Control Diets).

Some foods and flavors may be naturally appealing to infants and children, but there is strong evidence that food preferences vary considerably among individuals and cultures.  ”One man’s food is another man’s poison”. Roberts describes the interesting story of a Gaku Homma, Japanese cookbook author whose initial impression of Coke was  that it tasted “like medicine” and was repulsed by it. Similarly, Westerners are often repulsed by Asian fermented foods, or delicacies like dog or snake. Certain cultures find insects and grubs to be delectable, but most of us would probably pass, even knowing that such foods represent a nutritious source of calories.  There are many unfamiliar foods, rich in fat, sugar, salt or flavor, that the average fan of potato chips and ice cream would reject, even if hungry. For an interesting discussion of the cultural relativity of food acceptance and rejection of unfamiliar or novel foods, see the article by  John Prescott in the Encyclopedia of Food and Culture.

Likewise, over time we can learn to like flavors and tastes that were once unappealing.  Roberts cites experiments where rats that do not like the taste of saccharine, grow to like it when they are intravenously fed glucose.  There are many “acquired tastes” that we come to like only after repeated exposures.  Our palates are changeable.

If you think that food aromas are naturally or inherently appetizing, rather than relative, ask yourself: Why do we respond to food odors differently than other evocative and pleasant odors – flowers and plants, soil, sea, even pleasant or sensual human scents?  Smelling a rose does not make you hungry. Could we be conditioned to salivate and secrete insulin in response to the smell of a rose if we always sniffed a rose before gulping down a sweet drink? I think so. Pleasant aromas or tastes don’t necessarily generate a drive to eat.  The association between sensation and the drive to eat must be learned.

In fact, both Guyenet and Kessler appear to acknowledge the relativity of taste at certain points in their accounts.  For example, Guyenet notes that taste preferences towards beer or vegetables change as we transition from childhood to adulthood.  It is instructive that Guyenet defines “food reward” in a surprisingly  broad way:

Food reward is the process by which eating specific foods reinforces behaviors that favor the acquisition and consumption of the food in question.  You could also call rewarding food “reinforcing” or “habit-forming”, although not necessarily in an addictive sense.  Food reward is a perfectly normal and healthy part of life, although I believe it can be harmful if it exceeds the bounds of what we’re adapted to.  Food reward is essential for survival in a natural environment, because it teaches you what to eat and how to get it through a trial-and-error process. (Food reward, May 26, 2011)

In this definition of reward, Guyenet seems to move away from the idea that “reward” is an inherent property of food (i.e. fat, sugar, salt) in triggering opioids and dopamine, but rather is a result of conditioning. Sounding very similar to Roberts, Guyenet notes that

Researchers have demonstrated in rodents and humans that pairing a flavor with a source of calories makes us gradually enjoy the flavor more, whether or not it remains paired to calories afterward.  That’s called a “conditioned flavor preference”, and it’s a simple demonstration of food reward in action.  The brain senses the ingested calories and assigns a positive reward value to the cues (flavor, location, etc.) associated with the calories, after which we’ll be more likely to eat something that contains the preferred flavor.

As another example, rats prefer to hang around a place where they have repeatedly received rewarding food.  Have you ever seen a child run after an ice cream truck?  After a certain time, our motivation to obtain a food that we perceive as rewarding increases, and so does our consumption of it.  Rats accustomed to eating human junk food will endure foot shocks and extreme temperatures to obtain it, even when much healthier unprocessed rodent chow is freely available

Put another way:

It doesn’t matter whether or not you like the Little Debbie cake once it’s in your mouth.  It doesn’t matter how you feel afterward.  The only thing that matters is whether or not you’ll buy another one tomorrow.  That’s food reward.

Kessler also acknowledges the role of Pavlovian conditioning in appetite, recognizing that not just flavors, but any cues can serve as reinforcers.  In Chapter 10 of his book, he cites Pavlov’s success in training dogs to salivate in response to the ringing of a bell, even after it is no longer accompanied by food. Kessler discusses Kent Berridge’s related concept of “incentive salience” :

Simply put, incentive salience is the desire, activated by cues, for something that predicts reward.  It’s a learned association — we learn to want a food or some other substance we once liked…Cue-induced wanting, said Berridge is “triggered by the sight of a cookie or someone lighting up a cigarette nearby or clinking the ice cubes in the glass of alcohol…Those kinds of cues have the power to evoke the desire to take that thing again.” Experience imbues the cue with incentive salience. Positive emotions become embedded in cues, which then develop a force of their own. (The End of Overeating, Ch. 10)

So the door has been opened here to the idea that “reward” is not an inherent property of food but rather the consequence of a conditioned association or “pairing” between the calories in the food and a sensible signal or cue.  The cue could be a flavor, but it could just as well be a visual or auditory cue,  a familiar location or a social context.  In this understanding, “reward” not an inherent property of the food, but is rather a learned response to perceptual cues associated with the food.  These cues need only at some point to have become associated with a conditioned expectation of caloric value.

But now we come to the internal contradiction in the Kessler-Guyenet theory of food reward:  Is “reward” objective and invariant — or relative, subjective and variable?  It cannot be both. To say that reward is “relative” means that it varies markedly among individuals and across cultures, but that does not make it any less real.  It can be a powerfully motivating force, driving the obese to overeat and even binge to unhealthful extremes.  But to acknowledge the subjectivity and relativity of food reward is at odds with the idea that there is such thing as inherently “hyperpalatable” food that is irresistibly obesogenic in and of itself.

An alternative explanation: impaired metabolism.  I’m not denying here that people crave or get addicted to foods like potato chips, cookies and ice cream.  No doubt these people find the flavors salient and compelling, even to the point of addiction. But it’s not the flavor that causes the behavior in the first place. The flavor only becomes a strong cue under certain conditions.  That’s obvious from the simple fact that many people, eating the very same foods, do not find them to be addictive.  While I occasionally enjoy a cookie or some ice cream, I actually find it repulsive to eat more than a modest amount.  While I used to like soda, I now experience Coke as sickly sweet.  And I think I’m not alone in that reaction.

A more likely explanation is that food addicts have altered, perhaps even damaged, their metabolisms.   They are most likely insulin-resistant and leptin-resistant as a result of many possible factors, including obesity, stress and inflammation of their insulin receptors and glucose transporters.   Guyenet aptly describes how inflammation and lipotoxicity damage the hypothalamus:

There’s an additional factor that I’ve come to believe may be an “elephant in the room” when it comes to insulin/leptin resistance and chronic inflammation, and that is, ironically, energy excess.  Glucose and fatty acids, the body’s main two fuels, are toxic when present in the bloodstream in excess.  When someone eats too many calories, his body has to deal with the excess.  The healthiest way of doing this is actually to shunt the excess energy into fat tissue where it is inert.  If the fat tissue does not have a sufficient affinity for the excess fat, free fatty acid levels in the circulation may rise, and tissues and cells may accumulate fat and fat metabolites…if fat mass increases enough, fat cells become insulin resistant, release more fatty acids into the circulation and fail to clear fatty acids from the circulation after a mixed meal.  Essentially, fat tissue loses its formerly high affinity for excess fat, and these undesirable fat metabolites accumulate in lean tissues in a manner reminiscent of lipodystrophy.  This contributes to insulin resistance and glucose intolerance by the same mechanism described above, creating an excess of circulating glucose as well, which together with the excess of fatty acids can enhance chronic inflammation, further insulin resistance and damage the insulin-secreting pancreas.

…Therefore, it’s possible that an excess of circulating fatty acids (and perhaps glucose) itself acts to raise the setpoint through the gradual accumulation of fatty acid metabolites and inflammation in the hypothalamus, promoting leptin resistance and creating a “cascading failure” of energy balance regulation, glucose metabolism and inflammatory signaling.  This would explain why people in affluent societies have trouble staying lean as they age, as well as why obesity is so difficult to treat.  I think this is likely to be a late stage process, occurring after significant body fat accumulation and essentially “cementing” the increase in body fatness.  The early stage that causes the initial rise in body fatness probably has more to do with food reward/palatability/availability, although that should remain a factor even after obesity is well established…The basic idea is that in genetically susceptible people, excessive food reward/palatability/availability and inactivity cause overconsumption and an increase in the body fat setpoint, followed by the eventual accumulation of fat metabolites and inflammation in the hypothalamus, which exacerbate the problem and make it more difficult to treat.  Other factors, such as micronutrients, gut flora, fiber, fat quality, polyphenols, sleep and stress, may also play a role.  I think this is a reasonable working hypothesis of why obesity has increased so rapidly in the last 30 years, and is so difficult to treat once established.  I believe these ideas are broadly consistent with the research and opinions of senior obesity researchers I respect. (Roadmap to Obesity, August 25, 2011)

Cause and effect. Where I believe Guyenet goes wrong in the above passage is in postulating that “the early stage” of obesity is driven by primarily by food reward causing overconsumption, which then leads to obesity and leptin resistance.  I think the cause and effect relationship is reversed. Certainly “normal” reward is part of a healthy appetite, but that doesn’t lead to obesity.  It is the leptin resistance of obesity that sets one up for food reward to become pathogenic.   According to Robert Lustig, the normal satiating effect of insulin within the brain (CNS) becomes impaired in those with insulin and leptin resistance:

Although CNS insulin levels tend to reflect serum insulin levels, the relationship breaks down in obesity states. In obesity, there is proportionally less CNS insulin; the expression of the CNS insulin transporter is decreased in several obesity models. This paucity of insulin available for satiety signaling may represent a form of CNS insulin resistance. (Lustig, Fast Food, Central Nervous System Insulin Resistance, and Obesity)

Put simply, it takes more time and larger quantities food or beverage for insulin-resistant individuals to become sated, because the appetite-suppressing or “shut off” effect of insulin in the hypothalamus is impaired.  Added to this is the fact that obese, insulin-resistant individuals typically have a grossly amplified preprandial insulin response, which means that blood glucose is more easily stoked by mere appetite cues like the sight, aroma, or even thought of food.  Frequent, regular and familiar eating of these reward foods further strengthens the reinforcement.  Even stress can trigger this hunger cycle.  This leads to a very strong drive to start eating and great difficulty in shutting off the eating.  And with more overconsumption of food and the resultant obesity, a vicious cycle sets in, leading to heightened insulin-resistance and leptin-resistance.  Once this vicious cycle begins, the psychological component of food cravings and addictions is enhanced.  The association between flavor cues — or any cues — and consumption of the food is strengthened.  And the food becomes more and more palatable, even “hyperpalatable”.  But it is the impaired metabolism of obesity and the reinforcing eating patterns that make these foods hyperpalatable to the individual, not the other way around.

Foods are not inherently hyper-rewarding.  Rather, an impaired metabolism, combined with reinforcing eating patterns  lead to food becoming hyper-rewarding. 

I can anticipate the following objection to my argument:  Am I saying that any food can become hyperpalatable or addictive?  If so, why are foods like french fries, bread, cookies, chocolate and ice cream craved more than celery, cucumbers and lamb chops?   The answer, I think, is that if you are leptin-resistant and insulin-resistant, these high calorie foods provide a sufficiently rapid “bolus” injection of calories into the bloodstream to overcome any initial preprandial drop in blood glucose, and to spike insulin sufficiently high to overcome the CNS insulin resistance and thus satisfy appetite.  However–and this is a key point–not everyone finds junk foods to be irresistable.  Most insulin sensitive individuals are readily sated on pizza or dessert.  And not everyone even finds these foods to be enjoyable.

Another important factor in the addictiveness of food is the reduction or impairment in dopamine receptors in the brains of the obese, as documented by PET scans. Interestingly, a similar reduction in dopamine receptors is seen in drug addicts and depressed individuals.  This could be a result of the overstimulation by raised levels of dopamine from the “bolus” of large meals or binges. resulting in a homeostatic downregulation of receptors.  I’ve discussed this in more detail in my post Change your receptors, change your set point. Probably any large amount of calories, even with unfamiliar, less palatable, or weaker flavors would do the same trick.  For a short time, there would be frustration due to reduced dopamine signaling  — until the brain learned the new flavor-calorie association.

Bland food diet.   From his theory of food reward, Guyenet proposes a way out:  Eat bland foods.  He supports this by citing evidence that pre-industrial cultures such as the Kitavans eat a diet that is quite bland, despite being high in carbohydrates, and thereby they remain lean and healthy.  He references studies on the effects of bland food diets in lean and obese humans (by Hashim and Van Italie, and by Michael Cabanac) to support his thesis.

Investigators have known for decades that the cafeteria diet is a highly effective way of producing obesity in rodents, but what was interesting about this particular study from my perspective is that it compared the cafeteria diet to three other commonly used rodent diets: 1) standard, unpurified chow; 2) a purified/refined high-fat diet; 3) a purified/refined low-fat diet designed as a comparator for the high-fat diet. All three of these diets were given as homogeneous pellets, and the textures range from hard and fibrous (chow) to soft and oily like cookie dough (high-fat). The low-fat diet contains a lot of sugar, the high-fat diet contains a modest amount of sugar, and the chow diet contains virtually none. The particular high-fat diet in this paper  (45% fat, which is high for a rat) is commonly used to produce obesity in rats, although it’s not always very effective. The 60% fat version is more effective.

Consistent with previous findings, rats on every diet consumed the same number of calories over time… except the cafeteria diet-fed rats, which ate 30% more than any of the other groups. Rats on every diet gained fat compared to the unpurified chow group, but the cafeteria diet group gained much more than any of the others. There was no difference in fat gain between the purified high-fat and low-fat diets.

So in this paper, they compared two refined diets with vastly different carb:fat ratios and different sugar contents, and yet neither equaled the cafeteria diet in its ability to increase food intake and cause fat gain. The fat, starch and sugar content of the cafeteria diet was not able to fully explain its effect on fat gain. However, each diets’ ability to cause fat gain correlated with its respective food reward qualities. Refined diets high in fat or sugar caused fat gain in rats relative to unpurified chow, but were surpassed by a diet containing a combination of fat, sugar, starch, salt, free glutamate (umami), interesting textures and pleasant and invariant aromas.

Guyenet’s interpretation is that the rats ate more of the “cafeteria diet” because it was more palatable, presumably due to the higher fat, starch and sugar content, than the equally calorie dense blander diets. But this is not proven.  How do we know it was more “palatable”, if this is a subjective quality?  All we know is that more of the cafeteria diet was consumed.  We can of course define that as palatability, but that would make the argument circular.  The real question is:  Do we eat more calories because inherent “palatability” or taste characteristics?  Or do foods become  perceived as more palatable because of prior food experience, eating patterns and associations that modify neural circuitry and the drive to eat?  Palatability appears not to be something inherent in food, but rather something changeable. We do not know what diets or reinforcement schedules the rats were raised on before Cabanac’s conducted his experiments.

From these and other observations, Guyenet concludes:

Some people may be inclined to think “well, if food tastes bad, you eat less of it; so what!” Although that may be true to some extent, I don’t think it can explain the fact that bland diets affect the calorie intake of lean and obese people differently. To me, that implies that highly rewarding food increases the body fat setpoint in susceptible people, and that food with few rewarding properties allows them to return to a lean state. (Food Reward, A Dominant Factor in Obesity, Part II)

In recognizing that bland diets have different effects on the lean and the obese, Guyenet here seems to made a full retreat from asserting the explanatory power of food reward as a primary driver. The relativity of taste here reveals that it must be a consequence, not a determinant, of metabolism and neural conditioning.

What can we do?  If you believe that tasty food is inherently addictive, it is reasonable to seek out bland food, and avoid strong flavors, fat, sugar and salt.  But is this necessary?  Do we have to give up not just “junk foods” like Big Macs, french fries and ice cream — but also more healthful foods that are flavorful, fatty, sweet or salty? What about lamb curry (fatty and flavored), berries and cream (sweet and fatty) or salted steak?  I think not. Flavor, fat, salt and even a modest amount of sugar is not the seed of obesity.  Rather, it is the effect that foods have on our hormones and receptors that we should think about.  To avoid obesity, we should strive to maximize our insulin sensitivity and leptin sensitivity. This can be done by a variety of measures, discussed elsewhere on this blog, including:

• weight loss, particularly abdominal fat
• intermittent fasting
• avoiding inflammatory foods and toxins that impair receptor sensitivity
• supplementing with fish oil, magnesium and vitamin D for receptor health
• avoiding chronic stress, but pursuing intermittent, intense “good” stress, such as:
• > high intensity exercise
• > cold showers
• > brief thrills and unpleasant challenges

…

Bon apetit.

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!

Those of you who live in the San Francisco Bay Area may be interested in attending a talk I’ve been invited to give on May 18 in Palo Alto.  The topic is “Intermittent fasting for health and longevity”, and I plan to summarize both the recent science and the best practices for successful fasting.

UPDATE: A video of this talk is now posted HERE.

The venue for the talk is Palo Alto’s cutting-edge combination fitness studio and heath food cafe, The 3rd Door. Beyond providing a friendly environment to get fit and meet friends after workouts for a light meal or coffee, The 3rd Door is involved in community outreach through their well respected WANDA program to empower the financial independence of single mothers.

The fitness philosophy of the 3rd door and their director, Johnny Nguyen, resonates with my own views:

We know that exercise is good for us –it makes us stronger, boosts our mood, enhances our confidence, makes us look better, and improves our lives. We believe exercise should be strenuous and challenging but not impossible. Our luxurious training facility with première fitness experts and diverse range of fitness classes and restorative therapies offer something for everyone at every fitness level.

I’m excited about the growing interest in intermittent fasting as path to improved health and fitness, and for the opportunity to talk about it and perhaps meet some of you at the 3rd door.

Here are the event details:

“Intermittent Fasting for Health and Longevity”

by Todd Becker

7-8 p.m.

The 3rd Door
131 Lytton Avenue
Palo Alto, CA 94301
650.352.1241

Many people take daily supplements that include antioxidants such as Vitamins A, C, and E; beta carotene, coenzyme Q10, and alpha lipoic acid. I used to be one of them, convinced of the theory that supplementation with antioxidants is an effective way to neutralize harmful free radicals.  These free radicals, also called ROS or “reactive oxygen species”, can cause oxidative damage to cells and organs, and have been implicated in the pathogenesis of degenerative diseases such as cancer, heart disease, and Alzheimer’ disease.

However, study after study not only fails to show a consistent benefit, but in many cases documents positive harm from taking antioxidants. While I continue to believe that antioxidant supplementation is helpful in certain isolated cases of acute infection, tissue damage, or a damaged or aged metabolism, for most of us antioxidants are probably worthless. In fact, antioxidant supplements can interfere with and weaken the body’s inherent ability to mount an effective defense against oxidative damage and its contribution toward degenerative diseases.

I’ve resisted this conclusion because I could not make sense of it.  That is…until I came across recent research into the biochemistry and genetic regulation of the antioxidant response element (ARE). Fortunately the ARE provides us with an in-built adaptive stress response that combats oxidative stress and inflammation The ARE makes the need for antioxidants in the diet unnecessary — other than to keep our food fresh. Surprisingly, antioxidant supplements can impair our adaptive stress response.  But there’s much we can do to strengthen this response.

Fruits, vegetables and green tea. One of the strongest arguments for taking antioxidant supplements is the observation that consumption of fruits and vegetables reduces the levels of oxidative damage and associated degenerative diseases. This has been shown in both epidemiological studies and observational studies.  Similar benefits have been associated with the consumption of certain herbal compounds rich in polyphenols, such as green tea, garlic and curcumin.  The assumption has always been that these benefits can be attributed to the fact that many fruits, vegetables and herbs are rich sources of naturally occurring antioxidants. Therefore, it only makes sense that if you can’t get enough fruits and vegetables in your normal diet, supplementation with purified chemical forms of these antioxidants can boost those benefits.  But it turns out that the protective effects of fruits and vegetables are most likely not due to their antioxidant content, which is probably too weak and inconsistent to explain the health benefits.

But before discussing the real reason that fruits and vegetables have health benefits, let’s review what is known about supplementation with antioxidants.

Antioxidant supplementation studies. It may surprise you that numerous of clinical trials and metabolic studies show no benefit, or even harm, from using antioxidant supplements:

• A 2004 American Heart Association meta-analysis of 20 clinical trials showed no benefits for the use of Vitamins C, E and beta carotene in the prevention of heart attacks or strokes, and no reduction in mortality.  While they acknowledged that the scientific evidence from observational studies supports the conclusion that “a diet high in food sources of antioxidants and other cardioprotective nutrients” reduces the risk of CVD, they found no support for any benefits from the use of antioxidant vitamin supplements.  They did indicate that antioxidant supplementation may be useful in certain critical medical procedures, but not for routine dietary supplementation.
• A 2008 Cochrane Institute meta-analysis of 67 randomised clinical trials on antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) versus placebo or no intervention found no evidence that antioxidant supplements prevent mortality in healthy people or patients with various diseases
• A University of Washington randomized trial showed evidence of positive harm from antioxidants.  A cocktail of antioxidants added to the course of patients with high cholesterol and using statin-niacin therapy led to reduced levels of HDL and increased levels of coronary blockage .
• A Kansas State University study showed that administering antioxidants during exercise can impair muscle function by suppressing hydrogen peroxide, a key signaling compound.  This can lead to reduced blood flow in the muscle.
• A study at Cedars-Sinai Heart Institute showed that cardiac stem cells cells that were loaded with high doses of antioxidants developed genetic abnormalities that predispose to the development of cancer.
• A study comparing chemical Vitamin C with oranges containing an equivalent amount of Vitamin C given to test subjects showed that the blood from those who ingested the oranges could neutralize hydrogen peroxide (an oxidant) but those who ingested Vitamin C tablets failed to do so.

These results were at first puzzling to me.  How can it be that administering the same antioxidant chemicals ubiquitous in “protective” fruits, vegetables and herbs — the same chemicals which have been shown to neutralize oxidants in the test tube — appear to be ineffective or even harmful when taken as dietary supplements? What’s going on here?

The endogenous antioxidant defense. What is missing in the above picture is the role of our body’s own innate defenses system for handling toxic chemicals like free radicals. While our immune system handles invading organisms and large proteins, another system is needed to deal with chemical toxins. It’s called the xenobiotic metabolism; “xenobiotic” is Latin for “foreign to the organism”.  It consists of three “waves” of protective enzymes which neutralize dangerous chemicals, designated: Phase I, Phase II, and Phase III.  In Phase I the “xenobiotic response element” (XRE) chemically modifies the foreign toxins, which can sometimes make them even more reactive oxidants.  In Phase II, a set of antioxidant enzymes known as the “antioxidant response element” (ARE) neutralizes these toxins, including free radicals. Phase III involves further modifications and excretion.

The ARE is your body’s own endogenous antioxidant defense.  And it is far more powerful and effective than any antixodants you consume orally at mounting a defense against free radicals.  The ARE system is activated by the presence of oxidants in specific tissues in the body. These oxidative toxins are detected by transcription factors, most importantly Nrf2 (Nuclear factor (erythroid-derived 2)-like 2).

Nrf2 has been called the “master redox switch”.  It turns on a series of cytoprotective genes, which have been nicknamed “vitagenes” by U. Massachusetts toxicologist and hormesis researcher Edward Calabrese. These vitagenes upregulate the production of endogenous antioxidant enzymes that combat oxidative stress and inflammation. Collectively, they are known as the Phase II antioxidant enzymes:

• glutathione transferase
• glutathione peroxidase
• glucuronysyl transferase
• quinone reductase
• epoxide hydrolase
• superoxide dismutase
• gamma glutamylcysteine

So how can it be that supplementing with antioxidants can actually dampen the body’s internal antioxidant defense system?

Homeostatic compensation. As we’ve seen time and again in this blog, the body is an adaptive system.  The organism adjusts to maintain a relatively constant state: homeostasis. Provide it with external “help” and it will reduce the effort in building its own internal defenses.  Just as using corrective lenses will weaken the eye’s inherent ability to focus, and avoiding exposure to allergens will prevent the adaptive immune system from developing, it turns out that chronic consumption of exogenous antioxidants reduces the “pressure” on your adaptive stress response — specifically your ARE system — to gear up its own endogenous antioxidant defense system by producing adequate amounts of the the Phase II enzymes.  In biological terms, taking antioxidants leads to homeostatic downregulation of the antioxidant response element.  This actually makes biological sense:  Why should the organism expend precious energy and resources building a defense system if the defense is provided for “free” through diet or supplements?

A number of studies bear out this compensatory effect:

• A metabolic study in houseflies showed that administering Vitamin C (ascorbic acid), Vitamin E (alpha tocopherol) and beta-carotene caused a compensatory depression of  activity of key endogeneous antioxidant enzymes includiing superoxide dismutase, catalase, and glutathione. The administration of vitamins C and E also reduced life span. Granted that humans are not the same as flies, but we use the same enzymes to detoxify.
• A study of supplementation of cells with the antioxidant lipoic acid showed that it inhibits the antioxidant adaptive response triggered by treatment with UV-B light  The added lipoic acid decreases the intracellular oxidative signals necessary to develop the adaptive response in human mononuclear cells.
• A 2008 study at the University of Valencia showed that  Vitamin C supplementation hampered exercise endurance.  While Vitamin C reduces ROS levels in short term, it impairs the adaptive response by reducing transcription factors that enable mitochodria production, and inhibiting expression of antioxidant enzymes superoxide dismutase and glutathione peroxidase.
• A 2010 study showed antioxidants can cause neurodegeneration by inhibiting autophagy — an important process for removing damaged cellular material.  Inhibition of autophagy by antioxidants has a range of other potential negative consequences.

So it appears that, by consuming more antioxidants, we become dependent upon them and perversely reduce our innate ability to detoxify. With any let-up in the constant supply of external defenses, we become more vulnerable to oxidative and inflammatory attack. And the externally supplied antioxidants themselves are in any case much less effective than the endogenous ones.

But if the endogenous antioxidant defense system is so potent, what steps can we take to build it up?

Plant toxins to the rescue. Nature exhibits a wonderful phenomenon called “biological arms races”.  To defend against predators, plants or animals develop defenses, and often this involves the production of biological “poisons”.  To defend themselves againts pests and parasites, plants have evolved a set of mildly toxic substances that discourage, sicken, or even kill predators, from microbes and insets to mammals.  These toxic substances typically taste bad and can be irritating.  However, predators evolve to be able to tolerate at least some of these plant toxins, at least in moderate amounts.  They do this by developing detoxification systems.  Which is exactly what the ARE is!

Some plant toxins are too poisonous and deadly.  But, as Nietzsche said: “That which does not kill us makes us stronger”.  Biologically speaking, this is the principle of hormesis advocated on this blog, the principle by which small amounts of a stressor activates and strengthens our internal defenses, but excessive levels of the same stressor overwhelms these defenses.  Our ARE anti-toxin system will develop in response to virtually any toxic compound.  In principle, you could strengthen it by ingesting all kinds of chemical poisons. But why play roulette?  Humans have grown up for eons consuming a fairly regular supply of certain plants to which they have become habituated, plants that contain tolerable amounts of toxins which moderately stimulate the adaptive stress response, but not sufficiently to kill us.  Of course, there are still poisonous plants and mushrooms which exceed this threshold, so there is a continuum.  And probably some people and populations can tolerate more than others of certain plant toxins. But some of these plant toxins are well enough tolerated by most of us to prove reliably beneficial.

What are the good plant toxins? We refer to them as “phytochemicals” or “phytonutrients”.

There are a nearly infinite number of phytonutrients, most of them unknown and uncharacterized.  But a number of them have been studied for their impact on upgregulating the Phase II enzymes of the the ARE system, as Mattson et. al. have detailed..  Many of these compounds fall into the chemical class of polyphenols, more specifically flavonoids.  They are typically pigmented, bitter or spicy tasting molecules. A partial list includes:

• resveratrol – from red grapes, which turns on sirtuins and has broad cardiovascular, memory and anti-aging benefits
• sulforaphone – from broccoli, which turns on antioxidant and anticancer enzymes in the skin, arteries and stomach
• curcumin – from tumeric, inhibits transcription factors and kinases involved in cancer and inflammation
• green tea - a rich but variable source of bioflavinoids which have been shown to have anticancer and cardioprotective effects

Other polyphenolics that stimulate that Phase II enzyme system have been found in garlic, rosemary, ginko, bee propilis, and even…coffee!

What may have confused many researchers is that these polyphenolic flavonoid compounds in many cases have antioxidant properties.  This fact may have led to drawing the mistaken conclusion that they work because they are antioxidants in their own right.  And yet this antioxidant effect is not consistent — polyphenols and other phytochemicals sometimes function as pro-oxidants, dependent on the context and dosage.  I believe the evidence for their being hormetic stimulants of the endogenous ARE system is stronger than the case for thinking of them as antioxidants.   For example:

• A review of cell culture experiments with various polyphenols shows that their mechanisms of action goes beyond their intrinsic antioxidant properties, by indirectly stimulating enzyme transcription through the ARE system.
• Resveratrol seems to have its optimal effect at concentrations too low to be explained by an antioxidant effect. A metabolic study of resveratrol in heart cells, showed that even at very low (micromolar) concentrations, it upregulates endogenous “cytoprotective factors” — antioxidants and phase 2 enzymes such as superoxide dismutase, catalase, glutathione, glutathione reductase, glutathione peroxidase, glutathione S-transferase (GST), and NAD(P)H:quinone oxidoreductase-1 (NOQ1).
• An Israeli study showed that caratenoids in tomatoes activate the ARE transcription system, upregulating the phase II detoxification enzymes in a manner that is not correlated with the antioxidant potential of the caratenoids.   However, caratenoids appear to have an optimum level, above which they may be harmful.

Am I the only one challenging the paradigm that fruits and vegetables are good for us because they are rich in antioxidants?  Certainly not. Stephan Guyenet has likewise challenged this explanation, and highlighted the hormetic properties of plant polyphenols in an excellent two-part series on his Whole Health Source blog:

• Polyphenols, Hormesis and Disease: Part I
• Polyphenols, Hormesis and Disease: Part II

In his article, Guyenet mentions the interesting phenomenon that the hormetic effects of polyphenols tend to be non-specific:

One of the most interesting effects of hormesis is that exposure to one stressor can increase resistance to other stressors. For example, long-term consumption of high-polyphenol chocolate increases sunburn resistance in humans, implying that it induces a hormetic response in skin. Polyphenol-rich foods such as green tea reduce sunburn and skin cancer development in animals.

Another researcher who has come to similar conclusions as me is Robert Rountree.  If you had trouble following the science here and you have 90 minutes to spare, please do yourself a favor and click here listen to this extremely informative, lucid, and humorously entertaining lecture by Rountree that was presented at the 2010 Integrative Healtcare Symposium.  Unfortunately this is an audio recording so you’ll have to just imagine the slides, but not much is lost without the pictures because Rountree is such a vivid speaker:

CLICK HERE TO LISTEN:

“Beyond Antioxidants: Nutrigenomic Regulation of the Adaptive Stress Response“

by Dr. Robert Rountree

Rountree makes the very powerful point that the skin-protective effect of the sulforaphane in broccoli cannot be explained by its inherent chemical antioxidant properties. He cites a Johns Hopkins study in which broccoli extract applied to the skin of nude mice prevented oxidative damage from UV light for a period of several days, even after it was washed off the skin.  The absorbed sulforaphane could only act as an antioxidant for 30-60 minutes, at best a short-term effect. However, the induced upregulation of antioxidants in the skin protected the skin from UV for two days! To put it in chemistry terms: antioxidants are stoichiometric and used up quickly, whereas the endogenous antioxidant enzyme system is catalytic and long-lasting.

I’ll conclude by considering three interesting questions:

1. Why are there antioxidants and polyphenols in plants, vegetables and herbs?

Rountree suggests a plausible reason for why plants are rich in polyphenols: they act as natural pesticides. As I suggested above, this is part of the evolutionary arms race, and we’ve at least partially adapted to tolerate certain levels of these natural plant toxins.  But what about the antioxidants?  They don’t seem to protect the plant from predators, so why are they there?

I think the most plausible evolutionary reason for the presence of the antioxidants in plants is to protect the seeds in the fruit or vegetable against oxidative damage.  But this doesn’t take much antioxidant, as vegetables and fruit are relative “static” seed protectors.  They aren’t dynamic organisms requiring a long term sustained defense, as is the case with animals.

2.  If antioxidants are useless or even detrimental to our endogenous antioxidant defenses, should I take vitamins?

This is not a simple question, and I’m not your medical practitioner.  But a few things can be said here. First, antioxidant vitamins like Vitamin C (ascorbic acid) and E (tocopherols) are not merely antioxidants. They also perform certain other essential biological functions in processes such as collagen synthesis (Vitamin C), preventing scurvy, and protecting against lipid peroxidation in membranes. However, for these functions only very low amounts of the vitamin are required. By some estimates, 10 mg per day of Vitamin C will prevent scurvy, and 4 mg per day of Vitamin E will ensure good membrane function. The multi-gram  megadoses recommended by advocates of “orthomolecular medicine” such as Linus Pauling are based upon the antioxidant function of these molecules. In light of the studies showing that high levels of exogenous antioxdants suppress our innate endogenous Antioxidant Response Element, these high levels seem to me to be uncalled for, and likely to impair our native ability to handle oxidative stress.  The only exception I would make is in the case of acute or severe infection or illness, or advanced age, where the body’s own immune system and xenobiotic defense system may be compromised or unable to mount a sufficient defense on its own. But routine daily supplementation with antioxidants seems unwise if you are otherwise healthy and eat a good diet.

I’m also only addressing here the antioxidant vitamins and minerals, so this discussion is silent as to the wisdom of supplementation with other vitamins, such as Vitamins A, B and D, which are not classically considered to be antioxidants. Yet I think the general principle of hormesis should always be considered: that which is beneficial at a low or moderate dosage is often detrimental at higher doses. So be careful.

3.  What dietary guidelines can I follow to strengthen my endogenous antioxidant defense system?

What is most exciting for me is that I think I finally have a scientific reason to eat more and varied vegetables, fruits, herbs and spices! Coming from a generally low carb orientation, I’ve made sure to get plenty of protein and fat in my diet from meat, fish, dairy and nuts.  I happen to like broccoli, asparagus, brussell spouts, green and red peppers, and mushrooms, strawberries and blueberries.  But I always thought of them as something to liven up a low carb / Paleo diet with variety, texture and flavor, and perhaps add a little fiber.  I had heard the benefits of “phytonutrients” touted, but never heard a solid scientific reason for their nutritional value.  Thinking of them as hormetic “plant toxins” that help strengthen our internal defenses puts them in a new light.  This suggests a few guidelines to maximize hormetic stimulation of the ARE Phase II enzyme system:

• eat especially those vegetables and fruits with bright or intense colors (these contain bioflavonoids)
• eat fruits, skins and seeds which are bitter (these contain glucosinolates)
• consume teas, herbs and spices which have strong, bitter, or hot flavors
• to ensure hormesis, vary your choices, and limit the amount and frequency of any single fruit, vegetable or herb

Finally, the consider the activation of your in-built detoxification system — your ARE — as just one element of your adaptive stress response capability, which more broadly extends to your immune,  endocrine, nervous, and musculo-skeletal systems, and at a higher level — your psychology and spirit. The more we probe, the more it becomes apparent that we have within ourselves the ability to strengthen our defenses and take on increasing challenge. Relying on external supplements and external crutches is unwise except in the short term. The role of nutrition should be to build us up, not to replace — and thereby weaken — our internal defense, repair and growth capacities.

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.

This week I wrote a guest post about willpower for Julien Smith’s blog.  It synthesizes a number of the ideas on this blog about deconditioning urges and emotions that tend to undermine our resolve to make significant changes in life.

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.

………………………………….

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.