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 males, 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.
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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.
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