Why Do We Eat? A Neurobiological Perspective. Part IV

In this post, I'll follow up on the last post with a discussion two more important factors that can affect energy homeostasis and therefore our food intake and propensity to gain fat: age and menopause.

Age

Although it often isn't the case in non-industrial cultures, in affluent nations most people gain fat with age. This fat gain continues until old age, when many people once again lose fat. This is probably related to a number of factors, three of which I'll discuss. The first is that we tend to become less physically active with age. The second, related factor is that we lose lean mass with age, and so energy expenditure declines.

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What Puts Fat Into Fat Cells, and What Takes it Out?

Body fatness at its most basic level is determined by the rate of fat going into vs. out of fat cells. This in/out cycle occurs regardless of conditions outside the cell, but the balance between in and out is influenced by a variety of external factors. One of the arguments that has been made in the popular media about obesity goes something like this:


A number of factors can promote the release of fat from fat cells, including:

Epinephrine, norepinephrine, adrenocorticotropic hormone (ACTH), glucagon, thyroid-stimulating hormone, melanocyte-stimulating hormone, vasopressin, and growth hormone

But only two promote fat storage:

Insulin, and acylation-stimulating protein (ASP)*

Therefore if we want to understand body fat accumulation, we should focus on the latter category, because that's what puts fat inside fat cells. Simple, right?

Can you spot the logical error in this argument?

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Paleolithic Diet Clinical Trials, Part V

Dr. Staffan Lindeberg's group has published a new paleolithic diet paper in the journal Nutrition and Metabolism, titled "A Paleolithic Diet is More Satiating per Calorie than a Mediterranean-like Diet in Individuals with Ischemic Heart Disease" (1).

The data in this paper are from the same intervention as his group's 2007 paper in Diabetologia (2). To review the results of this paper, 12 weeks of a Paleolithic-style diet caused impressive fat loss and improvement in glucose tolerance, compared to 12 weeks of a Mediterranean-style diet, in volunteers with pre-diabetes or diabetes and ischemic heart disease. Participants who started off with diabetes ended up without it. A Paleolithic diet excludes grains, dairy, legumes and any other category of food that was not a major human food source prior to agriculture. I commented on this study a while back (3, 4).

One of the most intriguing findings in his 2007 study was the low calorie intake of the Paleolithic group. Despite receiving no instruction to reduce calorie intake, the Paleolithic group only ate 1,388 calories per day, compared to 1,823 calories per day for the Mediterranean group*. That's a remarkably low ad libitum calorie intake in the former (and a fairly low intake in the latter as well).

With such a low calorie intake over 12 weeks, you might think the Paleolithic group was starving. Fortunately, the authors had the foresight to measure satiety, or fullness, in both groups during the intervention. They found that satiety was almost identical in the two groups, despite the 24% lower calorie intake of the Paleolithic group. In other words, the Paleolithic group was just as full as the Mediterranean group, despite a considerably lower intake of calories. This implies to me that the body fat "set point" decreased, allowing a reduced calorie intake while body fat stores were burned to make up the calorie deficit. I suspect it also decreased somewhat in the Mediterranean group, although we can't know for sure because we don't have baseline satiety data for comparison.

There are a few possible explanations for this result. The first is that the Paleolithic group was eating more protein, a highly satiating macronutrient. However, given the fact that absolute protein intake was scarcely different between groups, I think this is unlikely to explain the reduced calorie intake.

A second possibility is that certain potentially damaging Neolithic foods (e.g., wheat and refined sugar) interfere with leptin signaling**, and removing them lowers fat mass by allowing leptin to function correctly. Dr. Lindeberg and colleagues authored a hypothesis paper on this topic in 2005 (5).

A third possibility is that a major dietary change of any kind lowers the body fat setpoint and reduces calorie intake for a certain period of time. In support of this hypothesis, both low-carbohydrate and low-fat diet trials show that overweight people spontaneously eat fewer calories when instructed to modify their diets in either direction (6, 7). More extreme changes may cause a larger decrease in calorie intake and fat mass, as evidenced by the results of low-fat vegan diet trials (8, 9). Chris Voigt's potato diet also falls into this category (10, 11). I think there may be something about changing food-related sensory cues that alters the defended level of fat mass. A similar idea is the basis of Seth Roberts' book The Shangri-La Diet.

If I had to guess, I would think the second and third possibilities contributed to the finding that Paleolithic dieters lost more fat without feeling hungry over the 12 week diet period.


*Intakes were determined using 4-day weighed food records.

**Leptin is a hormone produced by body fat that reduces food intake and increases energy expenditure by acting in the brain. The more fat a person carries, the more leptin they produce, and hypothetically this should keep body fat in a narrow window by this form of "negative feedback". Clearly, that's not the whole story, otherwise obesity wouldn't exist. A leading hypothesis is that resistance to the hormone leptin causes this feedback loop to defend a higher level of fat mass.

The Twinkie Diet for Fat Loss

The Experiment

I've received several e-mails from readers about a recent experiment by nutrition professor Mark Haub at Kansas State university (thanks to Josh and others). He ate a calorie-restricted diet in which 2/3 of his calories came from junk food: Twinkies, Hostess and Little Debbie cakes, Dorito corn chips and sweetened cereals (1). On this calorie-restricted junk food diet (800 calorie/day deficit), he lost 27 pounds in two months.

Therefore, junk food doesn't cause fat gain and the only thing that determines body fatness is how much you eat and exercise. Right?

Discussion

Let's start with a few things most people can agree on. If you don't eat any food at all, you will lose fat mass. If you voluntarily force-feed yourself with a large excess of food, you will gain fat mass, whether the excess comes from carbohydrate or fat (2). So calories obviously have something to do with fat mass.

But of course, the situation is much more subtle in real life. Since a pound of body fat contains roughly 3,500 calories, eating an excess of 80 calories per day (1 piece of toast) should lead to a weight gain of 8 lbs of fat per year. Conversely, if you're distracted and forget to eat your toast, you should lose 8 lbs of fat per year, which would eventually be dangerous for a lean person. That's why we all record every crumb of food we eat, determine its exact calorie content, and match that intake precisely with our energy expenditure to maintain a stable weight.

Oh wait, we don't do that? Then how do so many people maintain a stable weight over years and decades? And how do wild animals maintain a stable body fat percentage (except when preparing for hibernation) even in the face of food surpluses? How do lab rats and mice fed a whole food diet maintain a stable body fat percentage in the face of literally unlimited food, when they're in a small cage with practically nothing to do but eat?

The answer is that the body isn't stupid. Over hundreds of millions of years, we've evolved sophisticated systems that maintain "energy homeostasis". In other words, these systems act to regulate fat mass and keep it within the optimal range. The evolutionary pressures operating here are obvious: too little fat mass, and an organism will be susceptible to starvation; too much, and an organism will be less agile and less efficient at locomotion and reproduction. Energy homeostasis is such a basic part of survival that even the simplest organisms regulate it.

Not only is it clear that we have an energy homeostasis system, we even know a thing or two about how it works. Early studies showed that lesioning a part of the brain called the ventromedial hypothalamus causes massive obesity (3; this is also true in humans, when a disruption results from cancer). Investigators also discovered several genetic mutations in rats and mice that result in massive obesity*. Decades-long research eventually demonstrated that these models have something in common: they all interfere with an energy homeostasis circuit that passes information about fat mass to the hypothalamus via the hormone leptin.

The leptin system is a classic negative feedback loop: the more fat mass accumulates, the more leptin is produced. The more leptin is produced, the more the hypothalamus activates programs to reduce hunger and increase energy expenditure, which continues until fat mass is back in the optimal range. Conversely, low fat mass and low leptin lead to increased hunger and energy conservation by this same pathway**.

So if genetic mutants can become massively obese, I guess that argues against the idea that voluntary food intake and energy expenditure are the only determinants of fat mass. But a skeptic might point out that these are extreme cases, and such mutations are so rare in humans that the analogy is irrelevant.

Let's dig deeper. There are many studies in which rodents are made obese using industrial high-fat diets made from refined ingredients. The rats eat more calories (at least in the beginning), and gain fat rapidly. No big surprise there. But what may come as a surprise to the calorie counters is that rodents on these diets gain body fat even if their calorie intake is matched precisely to lean rodents eating a whole food diet (4, 5, 6). In fact, they sometimes gain almost as much fat as rodents who are allowed to eat all the industrial food they want. This has been demonstrated repeatedly.

How is this possible? The answer is that the calorie-matched rats reduce their energy expenditure to a greater degree than those that are allowed free access to food. The most logical explanation for this behavior is that the "set point" of the energy homeostasis system has changed. The industrial diet causes the rodents' bodies to "want" to accumulate more fat, therefore they will accomplish that by any means necessary, whether it means eating more, or if that's not possible, expending less energy. This shows that a poor diet can, in principle, dysregulate the system that controls energy homeostasis.

Well, then why did Dr. Haub's diet allow him to lose weight? The body can only maintain body composition in the face of a calorie deficit up to a certain point. After that, it has no choice but to lower fat mass. It will do so reluctantly, at the same time increasing hunger, and reducing lean mass***, muscular strength and energy dedicated to tissue repair and immune function. However, I hope everyone can agree that a sufficient calorie deficit can lead to fat loss regardless of what kind of food is eaten. Dr. Haub's 800 calorie deficit qualifies. I think only a very small percentage of people are capable of maintaining that kind of calorie deficit for more than a few months, because it is mentally and physically difficult to fight against what the hypothalamus has decided is in your best interest.

My hypothesis is that, in many people, industrial food and an unnatural lifestyle lead to gradual fat gain by dysregulating the energy homeostasis system. This "breaks" the system that's designed to automatically keep our fat mass in the optimal range by regulating energy intake, energy expenditure and the relative partitioning of energy resources between lean and fat tissue. This system is not under our conscious control, and it has nothing to do with willpower.

I suspect that if you put a group of children on this junk food diet for many years, and compared them to a group of children on a healthy diet, the junk food group would end up fatter as adults. This would be true if neither group paid any attention to calories, and perhaps even if calorie intake were identical in the two groups (as in the rodent example). The result of Dr. Haub's experiment does not contradict that hypothesis.

So do calories matter? Yes, but in a healthy person, all the math is done automatically by the hypothalamus and energy balance requires no conscious effort. In 2010, many people have already accumulated excess fat mass. How that may be sustainably lost is another question entirely, and a more challenging one in my opinion. As they say, an ounce of prevention is worth a pound of cure. There are many possible strategies, with varying degrees of efficacy that depend highly on individual differences, but I think overall the question is still open. I discussed some of my thoughts in a recent series on body fat regulation (7, 8, 9, 10, 11).


* ob/ob and db/db mice. Zucker and Koletsky rats. Equivalent mutations in humans also result in obesity.

** Via an increase in muscular efficiency and perhaps a decrease in basal metabolism. Thyroid hormone activity drops.

*** Loss of muscle, bone and connective tissue can be compensated for by strength training during calorie restriction. Presumed loss of other non-adipose tissues (liver, kidney, brain, etc.) is probably not affected by strength training.

Intervew with Chris Kresser of The Healthy Skeptic

Last week, I did an audio interview with Chris Kresser of The Healthy Skeptic, on the topic of obesity. We put some preparation into it, and I think it's my best interview yet. Chris was a gracious host. We covered some interesting ground, including (list copied from Chris's post):

• The little known causes of the obesity epidemic
• Why the common weight loss advice to �eat less and exercise more� isn�t effective
• The long-term results of various weight loss diets (low-carb, low-fat, etc.)
• The body-fat setpoint and its relevance to weight regulation
• The importance of gut flora in weight regulation
• The role of industrial seed oils in the obesity epidemic
• Obesity as immunological and inflammatory disease
• Strategies for preventing weight gain and promoting weight loss

Some of the information we discussed is not yet available on my blog. You can listen to the interview through Chris's post here.

Interview with John Barban

I recently did a podcast interview with John Barban from the Adonis Lifestyle blog. We talked mostly about fat mass and the body fat "setpoint". As it turns out, what I said must have been at odds with John's philosophy, because he posted another podcast the next week that appears to be about why he disagrees with me!

Anyway, enjoy the interview.

I did another one recently with Jimmy Moore that's coming soon.

The Body Fat Setpoint, Part IV: Changing the Setpoint

Prevention is Easier than Cure

Experiments in animals have confirmed what common sense suggests: it's easier to prevent health problems than to reverse them. Still, many health conditions can be improved, and in some cases reversed, through lifestyle interventions. It's important to have realistic expectations and to be kind to oneself. Cultivating a drill sergeant mentality will not improve quality of life, and isn't likely to be sustainable.

Fat Loss: a New Approach

If there's one thing that's consistent in the medical literature, it's that telling people to eat fewer calories does not help them lose weight in the long term. Gary Taubes has written about this at length in his book Good Calories, Bad Calories, and in his upcoming book on body fat. Many people who use this strategy see transient fat loss, followed by fat regain and a feeling of defeat. There's a simple reason for it: the body doesn't want to lose weight. It's extremely difficult to fight the fat mass setpoint, and the body will use every tool it has to maintain its preferred level of fat: hunger, reduced body temperature, higher muscle efficiency (i.e., less energy is expended for the same movement), lethargy, lowered immune function, et cetera.

Therefore, what we need for sustainable fat loss is not starvation; we need a treatment that lowers the fat mass setpoint. There are several criteria that this treatment will have to meet to qualify:

1. It must cause fat loss
2. It must not involve deliberate calorie restriction
3. It must maintain fat loss over a long period of time
4. It must not be harmful to overall health
   

I also prefer strategies that make sense from the perspective of human evolution.

Strategies: Diet Pattern

The most obvious treatment that fits all of my criteria is low-carbohydrate dieting. Overweight people eating low-carbohydrate diets generally lose fat and spontaneously reduce their calorie intake. In fact, in several diet studies, investigators compared an all-you-can-eat low-carbohydrate diet with a calorie-restricted low-fat diet. The low-carbohydrate dieters generally reduced their calorie intake and body fat to a similar or greater degree than the low-fat dieters, despite the fact that they ate all the calories they wanted (1). This suggest that their fat mass setpoint had changed. At this point, I think moderate carbohydrate restriction may be preferable to strict carbohydrate restriction for some people, due to the increasing number of reports I've read of people doing poorly in the long run on extremely low-carbohydrate diets (2).

Another strategy that appears effective is the "paleolithic" diet. In Dr. Staffan Lindeberg's 2007 diet study, overweight volunteers with heart disease lost fat and reduced their calorie intake to a remarkable degree while eating a diet consistent with our hunter-gatherer heritage (3). This result is consistent with another diet trial of the paleolithic diet in diabetics (4). In post hoc analysis, Dr. Lindeberg's group showed that the reduction in weight was apparently independent of changes in carbohydrate intake*. This suggests that the paleolithic diet has health benefits that are independent of carbohydrate intake.

Strategies: Gastrointestinal Health

Since the gastrointestinal (GI) tract is so intimately involved in body fat metabolism and overall health (see the former post), the next strategy is to improve GI health. There are a number of ways to do this, but they all center around four things:

1. Don't eat food that encourages the growth of harmful bacteria
2. Eat food that encourages the growth of good bacteria
3. Don't eat food that impairs gut barrier function
4. Eat food that promotes gut barrier health

The first one is pretty easy: avoid refined sugar, refined carbohydrate in general, and lactose if you're lactose intolerant. For the second and fourth points, make sure to eat fermentable fiber. In one trial, oligofructose supplements led to sustained fat loss, without any other changes in diet (5). This is consistent with experiments in rodents showing improvements in gut bacteria profile, gut barrier health, glucose tolerance and body fat mass with oligofructose supplementation (6, 7, 8).

Oligofructose is similar to inulin, a fiber that occurs naturally in a wide variety of plants. Good sources are jerusalem artichokes, jicama, artichokes, onions, leeks, burdock and chicory root. Certain non-industrial cultures had a high intake of inulin. There are some caveats to inulin, however: inulin and oligofructose can cause gas, and can also exacerbate gastroesophageal reflux disorder (9). So don't eat a big plate of jerusalem artichokes before that important date.

The colon is packed with symbiotic bacteria, and is the site of most intestinal fermentation. The small intestine contains fewer bacteria, but gut barrier function there is critical as well. The small intestine is where the GI doctor will take a biopsy to look for celiac disease. Celiac disease is a degeneration of the small intestinal lining due to an autoimmune reaction caused by gluten (in wheat, barley and rye). This brings us to one of the most important elements of maintaining gut barrier health: avoiding food sensitivities. Gluten and casein (in dairy protein) are the two most common offenders. Gluten sensitivity is widespread and typically undiagnosed (10).

Eating raw fermented foods such as sauerkraut, kimchi, yogurt and half-sour pickles also helps maintain the integrity of the upper GI tract. I doubt these have any effect on the colon, given the huge number of bacteria already present. Other important factors in gut barrier health are keeping the ratio of omega-6 to omega-3 fats in balance, eating nutrient-dense food, and avoiding the questionable chemical additives in processed food. If triglycerides are important for leptin sensitivity, then avoiding sugar and ensuring a regular source of omega-3 should aid weight loss as well.

Strategies: Micronutrients

As I discussed in the last post, micronutrient deficiency probably plays a role in obesity, both in ways that we understand and ways that we (or I) don't. Eating a diet that has a high nutrient density and ensuring a good vitamin D status will help any sustainable fat loss strategy. The easiest way to do this is to eliminate industrially processed foods such as white flour, sugar and seed oils. These constitute more than 50% of calories for the average Westerner.

After that, you can further increase your diet's nutrient density by learning to properly prepare grains and legumes to maximize their nutritional value and digestibility (11, 12; or by avoiding grains and legumes altogether if you wish), selecting organic and/or pasture-raised foods if possible, and eating seafood including seaweed. One of the problems with extremely low-carbohydrate diets is that they may be low in water-soluble micronutrients, although this isn't necessarily the case.

Strategies: Miscellaneous

In general, exercise isn't necessarily helpful for fat loss. However, there is one type of exercise that clearly is: high-intensity intermittent training (HIIT). It's basically a fancy name for sprints. They can be done on a track, on a stationary bicycle, using weight training circuits, or any other way that allows sufficient intensity. The key is to achieve maximal exertion for several brief periods, separated by rest. This type of exercise is not about burning calories through exertion: it's about increasing hormone sensitivity using an intense, brief stressor (hormesis). Even a ridiculously short period of time spent training HIIT each week can result in significant fat loss, despite no change in diet or calorie intake (13).

Anecdotally, many people have had success using intermittent fasting (IF) for fat loss. There's some evidence in the scientific literature that IF and related approaches may be helpful (14). There are different approaches to IF, but a common and effective method is to do two complete 24-hour fasts per week. It's important to note that IF isn't about restricting calories, it's about resetting the fat mass setpoint. After a fast, allow yourself to eat quality food until you're no longer hungry.

Insufficient sleep has been strongly and repeatedly linked to obesity. Whether it's a cause or consequence of obesity I can't say for sure, but in any case it's important for health to sleep until you feel rested. If your sleep quality is poor due to psychological stress, meditating before bedtime may help. I find that meditation has a remarkable effect on my sleep quality. Due to the poor development of oral and nasal structures in industrial nations, many people do not breathe effectively and may suffer from conditions such as sleep apnea that reduce sleep quality. Overweight also contributes to these problems.

I'm sure there are other useful strategies, but that's all I have for now. If you have something to add, please put it in the comments.


* Since reducing carbohydrate intake wasn't part of the intervention, this result is observational.

The Body Fat Setpoint, Part III: Dietary Causes of Obesity

What Caused the Setpoint to Change?

We have two criteria to narrow our search for the cause of modern fat gain:

1. It has to be new to the human environment
   
2. It has to cause leptin resistance or otherwise disturb the setpoint
   

Although I believe that exercise is part of a healthy lifestyle, it probably can't explain the increase in fat mass in modern nations. I've written about that here and here. There are various other possible explanations, such as industrial pollutants, a lack of sleep and psychological stress, which may play a role. But I feel that diet is likely to be the primary cause. When you're drinking 20 oz Cokes, bisphenol-A contamination is the least of your worries.

In the last post, I described two mechanisms that may contribute to elevating the body fat set point by causing leptin resistance: inflammation in the hypothalamus, and impaired leptin transport into the brain due to elevated triglycerides. After more reading and discussing it with my mentor, I've decided that the triglyceride hypothesis is on shaky ground*. Nevertheless, it is consistent with certain observations:

• Fibrate drugs that lower triglycerides can lower fat mass in rodents and humans
  
• Low-carbohydrate diets are effective for fat loss and lower triglycerides
• Fructose can cause leptin resistance in rodents and it elevates triglycerides (1)
• Fish oil reduces triglycerides. Some but not all studies have shown that fish oil aids fat loss (2)
  

Inflammation in the hypothalamus, with accompanying resistance to leptin signaling, has been reported in a number of animal studies of diet-induced obesity. I feel it's likely to occur in humans as well, although the dietary causes are probably different for humans. The hypothalamus is the primary site where leptin acts to regulate fat mass (3). Importantly, preventing inflammation in the brain prevents leptin resistance and obesity in diet-induced obese mice (3.1). The hypothalamus is likely to be the most important site of action. Research is underway on this.

The Role of Digestive Health

What causes inflammation in the hypothalamus? One of the most interesting hypotheses is that increased intestinal permeability allows inflammatory substances to cross into the circulation from the gut, irritating a number of tissues including the hypothalamus.

Dr. Remy Burcelin and his group have spearheaded this research. They've shown that high-fat diets cause obesity in mice, and that they also increase the level of an inflammatory substance called lipopolysaccharide (LPS) in the blood. LPS is produced by gram-negative bacteria in the gut and is one of the main factors that activates the immune system during an infection. Antibiotics that kill gram-negative bacteria in the gut prevent the negative consequences of high-fat feeding in mice.

Burcelin's group showed that infusing LPS into mice on a low-fat chow diet causes them to become obese and insulin resistant just like high-fat fed mice (4). Furthermore, adding 10% of the soluble fiber oligofructose to the high-fat diet prevented the increase in intestinal permeability and also largely prevented the body fat gain and insulin resistance from high-fat feeding (5). Oligofructose is food for friendly gut bacteria and ends up being converted to butyrate and other short-chain fatty acids in the colon. This results in lower intestinal permeability to toxins such as LPS. This is particularly interesting because oligofructose supplements cause fat loss in humans (6).

A recent study showed that blood LPS levels are correlated with body fat, elevated cholesterol and triglycerides, and insulin resistance in humans (7). However, a separate study didn't come to the same conclusion (8). The discrepancy may be due to the fact that LPS isn't the only inflammatory substance to cross the gut lining-- other substances may also be involved. Anything in the blood that shouldn't be there is potentially inflammatory.

Overall, I think gut dysfunction probably plays a major role in obesity and other modern metabolic problems. Insufficient dietary fiber, micronutrient deficiencies, excessive gut irritating substances such as gluten, abnormal bacterial growth due to refined carbohydrates (particularly sugar), and omega-6:3 imbalance may all contribute to abnormal gut bacteria and increased gut permeability.

The Role of Fatty Acids and Micronutrients

Any time a disease involves inflammation, the first thing that comes to my mind is the balance between omega-6 and omega-3 fats. The modern Western diet is heavily weighted toward omega-6, which are the precursors to some very inflammatory substances (as well as a few that are anti-inflammatory). These substances are essential for health in the correct amounts, but they need to be balanced with omega-3 to prevent excessive and uncontrolled inflammatory responses. Animal models have repeatedly shown that omega-3 deficiency contributes to the fat gain and insulin resistance they develop when fed high-fat diets (9, 10, 11).

As a matter of fact, most of the papers claiming "saturated fat causes this or that in rodents" are actually studying omega-3 deficiency. The "saturated fats" that are typically used in high-fat rodent diets are refined fats from conventionally raised animals, which are very low in omega-3. If you add a bit of omega-3 to these diets, suddenly they don't cause the same metabolic problems, and are generally superior to refined seed oils, even in rodents (12, 13).

I believe that micronutrient deficiency also plays a role. Inadequate vitamin and mineral status can contribute to inflammation and weight gain. Obese people typically show deficiencies in several vitamins and minerals. The problem is that we don't know whether the deficiencies caused the obesity or vice versa. Refined carbohydrates and refined oils are the worst offenders because they're almost completely devoid of micronutrients.

Vitamin D in particular plays an important role in immune responses (including inflammation), and also appears to influence body fat mass. Vitamin D status is associated with body fat and insulin sensitivity in humans (14, 15, 16). More convincingly, genetic differences in the vitamin D receptor gene are also associated with body fat mass (17, 18), and vitamin D intake predicts future fat gain (19).

Exiting the Niche

I believe that we have strayed too far from our species' ecological niche, and our health is suffering. One manifestation of that is body fat gain. Many factors probably contribute, but I believe that diet is the most important. A diet heavy in nutrient-poor refined carbohydrates and industrial omega-6 oils, high in gut irritating substances such as gluten and sugar, and a lack of direct sunlight, have caused us to lose the robust digestion and good micronutrient status that characterized our distant ancestors. I believe that one consequence has been the dysregulation of the system that maintains the fat mass "setpoint". This has resulted in an increase in body fat in 20th century affluent nations, and other cultures eating our industrial food products.

In the next post, I'll discuss my thoughts on how to reset the body fat setpoint.


* The ratio of leptin in the serum to leptin in the brain is diminished in obesity, but given that serum leptin is very high in the obese, the absolute level of leptin in the brain is typically not lower than a lean person. Leptin is transported into the brain by a transport mechanism that saturates when serum leptin is not that much higher than the normal level for a lean person. Therefore, the fact that the ratio of serum to brain leptin is higher in the obese does not necessarily reflect a defect in transport, but rather the fact that the mechanism that transports leptin is already at full capacity.

The Body Fat Setpoint

One pound of human fat contains about 3,500 calories. That represents roughly 40 slices of toast. So if you were to eat one extra slice of toast every day, you would gain just under a pound of fat per month. Conversely, if you were to eat one fewer slice per day, you'd lose a pound a month. Right? Not quite.

How is it that most peoples' body fat mass stays relatively stable over long periods of time, when an imbalance of as little as 5% of calories should lead to rapid changes in weight? Is it because we do complicated calculations in our heads every day, factoring in basal metabolic rate and exercise, to make sure our energy intake precisely matches expenditure? Of course not. We're gifted with a sophisticated system of hormones and brain regions that do the calculations for us unconsciously*.

When it's working properly, this system precisely matches energy intake to expenditure, ensuring a stable and healthy fat mass. It does this by controlling food seeking behaviors, feelings of fullness and even energy expenditure by heat production and physical movements. If you eat a little bit more than usual at a meal, a properly functioning system will say "let's eat a little bit less next time, and also burn some of it off." This is why animals in their natural habitat are nearly always at an appropriate weight, barring starvation. The only time wild animals are overweight enough to compromise maximum physical performance is when it serves an important purpose, such as preparing for hibernation.

I recently came across a classic study that illustrates these principles nicely in humans, titled "Metabolic Response to Experimental Overfeeding in Lean and Overweight Healthy Volunteers", by Dr. Erik O. Diaz and colleagues (1). They overfed lean and modestly overweight volunteers 50% more calories than they naturally consume, under controlled conditions where the investigators could be confident of food intake. Macronutrient composition was 12-42-46 % protein-fat-carbohydrate.

After 6 weeks of massive overfeeding, both lean and overweight subjects gained an average of 10 lb (4.6 kg) of fat mass and 6.6 lb (3 kg) of lean mass. Consistent with what one would expect if the body were trying to burn off excess calories and return to baseline fat mass, the metabolic rate and body heat production of the subjects increased.

Following overfeeding, subjects were allowed to eat however much they wanted for 6 weeks. Both lean and overweight volunteers promptly lost 6.2 of the 10 lb they had gained in fat mass (61% of fat gained), and 1.5 of the 6.6 lb they had gained in lean mass (23%). Here is a graph showing changes in fat mass for each individual that completed the study:

We don't know if they would have lost the remaining fat mass in the following weeks because they were only followed for 6 weeks after overfeeding, although it did appear that they were reaching a plateau slightly above their original body weight. Thus, nearly all subjects "defended" their original body fat mass irrespective of their starting point. Underfeeding studies have shown the same phenomenon: whether lean or overweight, people tend to return to their original fat mass after underfeeding is over. Again, this supports the idea that the body has a body fat mass "set point" that it attempts to defend against changes in either direction. It's one of many systems in the body that attempt to maintain homeostasis.

OK, so why do we care?

We care because this has some very important implications for human obesity. With such a powerful system in place to keep body fat mass in a narrow range, a major departure from that range implies that the system isn't functioning correctly. In other words, obesity has to result from a defect in the system that regulates body fat, because a properly functioning system would not have allowed that degree of fat gain in the first place.

So yes, we are gaining weight because we eat too many calories relative to energy expended. But why are we eating too many calories? Because the system that should be defending a low fat mass is now defending a high fat mass. Therefore, the solution is not simply to restrict calories, or burn more calories through exercise, but to try to "reset" the system that decides what fat mass to defend. Restricting calories isn't necessarily a good solution because the body will attempt to defend its setpoint, whether high or low, by increasing hunger and decreasing its metabolic rate. That's why low-calorie diets, and most diets in general, typically fail in the long term. It's miserable to fight hunger every day.

This raises two questions:

1. What caused the system to defend a high fat mass?
2. Is it possible to reset the fat mass setpoint, and how would one go about it?
   

Given the fact that body fat mass is much higher in many affluent nations than it has ever been in human history, the increase must be due to factors that have changed in modern times. I can only speculate what these factors may be, because research has not identified them to my knowledge, at least not in humans. But I have my guesses. I'll expand on this in the next post.


* The hormone leptin and the hypothalamus are the ringleaders, although there are many other elements involved, such as numerous gut-derived peptides, insulin, and a number of other brain regions.

Eicosanoids, Fatty Liver and Insulin Resistance

I have to take a brief intermission from the heart disease series to write about a very important paper I just read in the journal Obesity, "COX-2-mediated Inflammation in Fat is Crucial for Obesity-linked Insulin Resistance and Fatty Liver". It's actually related to cardiovascular disease, although indirectly.

First, some background. Polyunsaturated fatty acids (PUFA) come mostly from omega-6 and omega-3 sources. Omega-6 and omega-3 are precursors to eicosanoids, a large and poorly understood class of signaling molecules that play a role in basically everything. Eicosanoids are either omega-6-derived or omega-3-derived. Omega-6 and omega-3 compete for the enzymes that convert PUFA into eicosanoids. Therefore, the ratio of omega-6 to omega-3 in tissues (related to the ratio in the diet) determines the ratio of omega-6-derived eicosanoids to omega-3-derived eicosanoids.

Omega-6 eicosanoids are very potent and play a central role in inflammation. They aren't "bad", in fact they're essential, but an excess of them is probably not good. Omega-3 eicosanoids are generally less potent, less inflammatory, and tend to participate in long-term repair processes. So in sum, the ratio of omega-6 to omega-3 in the diet will determine the potency and quality of eicosanoid signaling, which will determine an animal's susceptibility to inflammation-mediated disorders.

One of the key enzymes in the pathway from PUFA to eicosanoids (specifically, a subset of them called prostanoids) is cyclooxygenase (COX). COX-1 is expressed all the time and serves a "housekeeping" function, while COX-2 is induced by cellular stressors and contributes to the the formation of inflammatory eicosanoids. Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen inhibit COX enzymes, which is why they are effective against inflammatory problems like pain and fever. They are also used as a preventive measure against cardiovascular disease. Basically, they reduce the excessive inflammatory signaling promoted by a diet with a poor omega-6:3 balance. You wouldn't need to inhibit COX if it were producing the proper balance of eicosanoids to begin with.

Dr. Kuang-Chung Shih's group at the Department of Internal Medicine in Taipei placed rats on five different diets:

1. A control diet, eating normal low-fat rat chow.


2. A "high-fat diet", in which 45% of calories came from a combination of industrial lard and soybean oil, and 17% of calories came from sucrose*.


3. A "high-fat diet" (same as above), plus the COX-2 inhibitor celecoxib (Celebrex).


4. A "high-fat diet" (same as above), plus the COX-2 inhibitor mesulid.


5. An energy-restricted "high-fat diet".

The "high-fat diets", besides being high in sucrose (table sugar), also presumably had a poor omega-6:3 ratio, in the neighborhood of 10:1 or possibly higher. Weight and fat mass in rats and humans increases with increasing omega-6 in the diet, and also increases with a high 6:3 ratio. I wrote about that here. Rats eating the high-fat diets (groups 2- 4) gained weight as expected**.

Rats in group 2 not only gained weight, they also experienced increased fasting glucose, leptin, insulin, triglycerides, blood pressure and a massive decline in insulin sensitivity (seven-fold relative to group 1). Rats in groups 3 and 4 gained weight, but saw much less of a deterioration in insulin and leptin sensitivity, and blood pressure. Group 2 also developed fatty liver, which was attenuated in groups 3 and 4. If you're interested, group 5 (energy restricted high-fat) was similar to groups 3 and 4 on pretty much everything, including insulin sensitivity.

So there you have it folks: direct evidence that insulin resistance, leptin resistance, high blood pressure and fatty liver are mediated by excessive inflammatory eicosanoid signaling. I wrote about something similar before when I reviewed a paper showing that fish oil reverses many of the consequences of a high-vegetable oil, high-sugar diet in rats. I also reviewed two papers showing that in pigs and rats, a high omega-6:3 ratio promotes inflammation (mediated by COX-2) and lipid peroxidation in the heart. Are you going to quench the fire by taking drugs, or by reducing your intake of omega-6 and ensuring an adequate intake of omega-3?

*Of course, they didn't mention the sucrose in the methods section. I had to go digging around for the diet's composition. This is typical of papers on "high-fat diets". They load them up with sugar, and blame everything on the fat.

**Rats gain fat mass when fed a high-fat diet (even if it's not loaded with sugar). But humans don't necessarily gain weight on a high-fat diet (i.e. low-carb weight loss diet). What's the difference? Low-carbohydrate diet trials indicate that humans spontaneously reduce their caloric intake when eating low carbohydrate, high-fat food.

Leptin Resistance and Sugar

Leptin is a major hormone regulator of fat mass in vertebrates. It's a frequent topic on this blog because I believe it's central to overweight and modern metabolic disorders. Here's how it works. Leptin is secreted by fat tissue, and its blood levels are proportional to fat mass. The more fat tissue, the more leptin. Leptin reduces appetite, increases fat release from fat tissue and increases the metabolic rate. Normally, this creates a "feedback loop" that keeps fat mass within a fairly narrow range. Any increase in fat tissue causes an increase in leptin, which burns fat tissue at an accelerated rate. This continues until fat mass has decreased enough to return leptin to its original level.

Leptin was first identified through research on the "obese" mutant mouse. The obese strain arose by a spontaneous mutation, and is extremely fat. The mutation turned out to be in a protein investigators dubbed leptin. When researchers first discovered leptin, they speculated that it could be the "obesity gene", and supplemental leptin a potential treatment for obesity. They later discovered (to their great chagrin) that obese people produce much more leptin than thin people, so a defeciency of leptin was clearly not the problem, as it was in the obese mouse. They subsequently found that obese people scarcely respond to injected leptin by reducing their food intake, as thin people do. They are leptin resistant. This makes sense if you think about it. The only way a person can gain significant fat mass is if the leptin feedback loop isn't working correctly.

Another rodent model of leptin resistance arose later, the "Zucker fatty" rat. Zucker rats have a mutation in the leptin receptor gene. They secrete leptin just fine, but they don't respond to it because they have no functional receptor. This makes them an excellent model of complete leptin resistance. What happens to Zucker rats? They become obese, hypometabolic, hyperphagic, hypertensive, insulin resistant, and they develop blood lipid disturbances. It should sound familiar; it's the metabolic syndrome and it affects 24% of Americans (CDC NHANES III). Guess what's the first symptom of impending metabolic syndrome in humans, even before insulin resistance and obesity? Leptin resistance. This makes leptin an excellent contender for the keystone position in overweight and other metabolic disorders.

I've mentioned before that the two most commonly used animal models of the metabolic syndrome are both sugar-fed rats. Fructose, which accounts for 50% of table sugar and 55% of high-fructose corn syrup, is probably the culprit. Glucose, which is the remainder of table sugar and high-fructose corn syrup, and the product of starch digestion, does not have the same effects. I think it's also relevant that refined sugar contains no vitamins or minerals whatsoever. Sweetener consumption in the U.S. has increased from virtually nothing in 1850, to 84 pounds per year in 1909, to 119 pounds in 1970, to 142 pounds in 2005 (source).

In a recent paper, Dr. Philip Scarpace's group (in collaboration with Dr. Richard Johnson), showed that a high-fructose diet causes leptin resistance in rats. The diet was 60% fructose, which is extreme by any standards, but it caused a complete resistance to the effect of leptin on food intake. Normally, leptin binds receptors in a brain region called the hypothalamus, which is responsible for food intake behaviors (including in humans). This accounts for leptin's ability to reduce food consumption. Fructose-fed rats did not reduce their food intake at all when injected with leptin, while rats on a normal diet did. When subsequently put on a high-fat diet (60% lard), rats that started off on the fructose diet gained more weight.

I think it's worth mentionong that rodents don't respond to high-fat diets in the same way as humans, as judged by the efficacy of low-carbohydrate diets for weight loss. Industrial lard also has a very poor ratio of omega-6 to omega-3 fats (especially if it's hydrogenated), which may also contribute to the observed weight gain.

Fructose-fed rats had higher cholesterol and twice the triglycerides of control-fed rats. Fructose increases triglycerides because it goes straight to the liver, which makes it into fat that's subsequently exported into the bloodstream. Elevated triglycerides impair leptin transport from the blood to the hypothalamus across the blood-brain barrier, which separates the central nervous system from the rest of the body. Fructose also impaired the response of the hypothalamus to the leptin that did reach it. Both effects may contribute to the leptin resistance Dr. Scarpace's group observed.

Just four weeks of fructose feeding in humans (1.5g per kg body weight) increased leptin levels by 48%. Body weight did not change during the study, indicating that more leptin was required to maintain the same level of fat mass. This may be the beginning of leptin resistance.

How to Give a Rat Metabolic Syndrome

I was doing my usual journal rounds today when I came across an article in the American Journal of Hypertension that caught my eye. It's called "Metabolic Syndrome: Comparison of the Two Commonly Used Animal Models." Metabolic syndrome is a cluster of symptoms including large waist circumference, elevated triglycerides, elevated blood pressure, and insulin resistance. It's the quintissential modern metabolic disorder, and it affects 24% of Americans (NHANES III). So what are the two most commonly used animal models of metabolic syndrome?

• A strain called the spontaneously hypertensive rat (SHR), fed a high-sucrose (table sugar, 50% fructose) diet.
• Sprague-Dawley (generic lab strain) rats fed a high-fructose diet.

When fed sugar, these rats develop insulin resistance, impaired glucose tolerance, elevated triglycerides and hypertension. Fructose causes leptin resistance in rats. Leptin resistance causes metabolic syndrome in rats. These studies trace a line directly from sugar to the metabolic syndrome.

On to humans. Total sugar and fructose consumption have been increasing in the U.S. in recent decades, along with metabolic syndrome. I think the average numbers may hide some important information, because there is a fraction of the population that consumes far more than the average amount of sugar through soda. Leptin resistance seems to be central to the metabolic syndrome, and typically precedes the other symptoms. The evidence suggests that the rat research on metabolic syndrome is applicable to humans.

I don't think sugar acts alone in causing the metabolic syndrome in humans. I believe the liver is a central player in the disorder, as many of the markers used to diagnose it are measures of processes that occur in the liver (triglyceride synthesis, glucose and insulin disposal). Insulin resistance in the liver is sufficient to cause many of the hallmarks of the metabolic syndrome in mice. The fructose portion of sugar and high-linoleic (omega-6) vegetable oils act synergistically to cause liver dysfunction in rats and probably humans.

I also believe wheat contributes to the process, perhaps through its ability to cause hyperphagia (overeating) or intestinal damage. So we're back to the three big killers in the modern diet:

• Refined vegetable oils
• Sugar
• Wheat
  

Hyperphagia

One of the things I didn't mention in the last post is that Americans are eating more calories than ever before. According to Centers for Disease Control NHANES data, in 2000, men ate about 160 more calories per day, and women ate about 340 more than in 1971. That's a change of 7% and 22%, respectively. The extra calories come almost exclusively from refined grains, with the largest single contribution coming from white wheat flour (correction: the largest single contribution comes from corn sweeteners, followed by white wheat flour).

Some people will see those data and decide the increase in calories is the explanation for the expanding American waistline. I don't think that's incorrect, but I do think it misses the point. The relevant question is "why are we eating more calories now than we were in 1971?"

We weren't exactly starving in 1971. And average energy expenditure, if anything, has actually increased. So why are we eating more? I believe that our increased food intake, or hyperphagia, is the result of metabolic disturbances, rather than the cause of them.

Humans, like all animals, have a sophisticated system of hormones and brain regions whose function is to maintain a proper energy balance. Part of the system's job is to keep fat mass at an appropriate level. With a properly functioning system, feedback loops inhibit hunger once fat mass has reached a certain level, and also increase resting metabolic rate to burn excess calories. If the system is working properly, it's very difficult to gain weight. There have been a number of overfeeding studies in which subjects have consumed huge amounts of excess calories. Some people gain weight, many don't.

The fact that fat mass is hormonally regulated can be easily seen in other mammals. When was the last time you saw a fat squirrel in the springtime? When was the last time you saw a thin squirrel in the fall? These events are regulated by hormones. A squirrel in captivity will put on weight in the fall, even if its daily food intake is not changed.

A key hormone in this process is leptin. Leptin levels are proportional to fat mass, and serve to inhibit hunger and eating behaviors. Under normal conditions, the more fat tissue a person has, the more leptin they will produce, and the less they will eat until the fat mass has reached the body's preferred 'set-point'. The problem is that overweight Westerners are almost invariably leptin-resistant, meaning their body doesn't respond to the signal to stop eating!

Leptin resistance leads to hyperphagia, overweight and the metabolic syndrome (a common cluster of symptoms that implies profound metabolic disturbance). It typically precedes insulin resistance during the downward slide towards metabolic syndrome.

I suspect that wheat, sugar and perhaps other processed foods cause hyperphagia. It's the same thing you see when wheat is first introduced to a culture, even if it's replacing another refined carbohydrate. I believe hyperphagia is secondary to a disturbed metabolism. There's something about the combination of refined wheat, sugar, processed vegetable oils and other industrial foods that reached a critical mass in the mid-70s. The shift in diet composition disturbed our normal hormonal profile (even more than it was already disturbed), and sent us into a tailspin of excessive eating and unprecedented weight gain.

Two Things that Get on My Nerves, Part I

The "Thrifty Gene" Hypothesis

The thrifty gene hypothesis is the darling of many obesity researchers. It was proposed in 1962 by the geneticist James V. Neel to explain the high rates of obesity in modern populations, particularly modernizing American Indians. It states that our species evolved under conditions of frequent starvation, so we're designed to store every available calorie. In today's world of food abundance, our bodies continue to be thrifty and that's why we're fat.  You practically can't read a paper on overweight without seeing an obligatory nod to the thrifty gene hypothesis. The only problem is, it doesn't make much sense.

The assumption that hunter-gatherers and non-industrial agriculturalists lived under chronic calorie deprivation isn't well supported. The anthropological evidence indicates that most hunter-gatherers had abundant food, most of the time. They did have fluctuations in energy balance, but the majority of the time they had access to more calories than they needed. Yet they were not fat.

The Kitavans are a good example. They are a horticultural society that eats virtually no grains or processed food. In Dr. Staffan Lindeberg's studies, he has determined that overweight is virtually nonexistent among them, despite an abundant food supply.

The cause of obesity is not the availability of excess calories, it's the deregulation of the bodyweight homeostasis system. We have a very sophisticated set of feedback loops that "try" to maintain a healthy weight. It's composed of hormones (leptin, insulin, etc.), certain brain regions, and many other elements, known and unknown. These feedback loops influence what the body does with calories, as well as feeding behaviors. When you throw a wrench in the gears with a lifestyle that is unnatural to the human metabolism, you deregulate the system so that it no longer maintains an appropriate "set-point".

Here's what Neel had to say about the thrifty gene hypothesis in 1982 (excerpts from Good Calories, Bad Calories):

The data on which that (rather soft) hypothesis was based has now largely collapsed.

And what does he think causes overweight in American Indians now?

The composition of the diet, and more specifically the use of highly refined carbohydrates.

RIP, thrifty gene.

Leptin

I've been puzzled by an interesting question lately. Why is it that certain cultures are able to eat large amounts of carbohydrate and remain healthy, while others suffer from overweight and disease? How do the pre-industrial Kuna and Kitavans maintain their insulin sensitivity while their bodies are being bombarded by an amount of carbohydrate that makes the average American look like a bowling ball?

I read a very interesting post on the Modern Forager yesterday that sent me on a nerd safari through the scientific literature. The paper that inspired the Modern Forager post is a review by Dr. Staffan Lindeberg. In it, he attempts to draw a link between compounds called lectins, found in grains (among other things), and resistance to the hormone leptin. Let's take a step back and go over some background.

One of the most-studied animal models of obesity is called the "Zucker" rat. This rat has a missense mutation in its leptin receptor gene, causing it to be nonfunctional. Leptin is a hormone that signals satiety, or fullness. It's secreted by fat tissue. The more fat tissue an animal has, the more leptin it secretes. Normally, this creates negative feedback that causes it to eat less when fat begins to accumulate, keeping its weight within a narrow range.

Zucker rats secrete leptin just fine, but they lack leptin receptors in their brain. Their blood leptin is high but their brain isn't listening. Thus, the signal to stop eating never gets through and they eat themselves to morbid obesity. Cardiovascular disease and diabetes follow shortly thereafter, unless you remove their visceral fat surgically.

The reason Zucker rats are so interesting is they faithfully reproduce so many features of the disease of civilization in humans. They become obese, hypometabolic, develop insulin resistance, impaired glucose tolerance, dyslipidemia, diabetes, and cardiovascular disease. Basically, severe metabolic syndrome. So here's a rat that shows that leptin resistance can cause something that looks a whole heck of a lot like the disease of civilization in humans.

For this model to be relevant to us, we'd expect that humans with metabolic syndrome should be leptin-resistant. Well what do you know, administering leptin to obese people doesn't cause satiety like it does in thin people. Furthermore, elevated leptin predicts the onset of obesity and metabolic syndrome. It also predicts insulin resistance. Yes, you read that right, leptin resistance may come before insulin resistance.

Interestingly enough, the carbohydrate-loving Kitavans don't get elevated leptin like europeans do, and they don't become overweight, develop insulin dysfunction or the metabolic syndrome either. This all suggests that leptin may be the keystone in the whole disease process, but what accounts for the differences in leptin levels between populations?