The Body Fat Setpoint, Part II: Mechanisms of Fat Gain

The Timeline of Fat Gain

Modern humans are unusual mammals in that fat mass varies greatly between individuals. Some animals carry a large amount of fat for a specific purpose, such as hibernation or migration. But all individuals of the same sex and social position will carry approximately the same amount of fat at any given time of year. Likewise, in hunter-gatherer societies worldwide, there isn't much variation in body weight-- nearly everyone is lean. Not necessarily lean like Usain Bolt, but not overweight.

Although overweight and obesity occurred forty years ago in the U.S. and U.K., they were much less common than today, particularly in children. Here are data from the U.S. Centers for Disease Control NHANES surveys (from this post):

Together, this shows that a) leanness is the most natural condition for the human body, and b) something about our changing environment, not our genes, has caused our body fat to grow.

Fat Mass is Regulated by a Feedback Circuit Between Fat Tissue and the Brain

In the last post, I described how the body regulates fat mass, attempting to keep it within a narrow window or "setpoint". Body fat produces a hormone called leptin, which signals to the brain and other organs to decrease appetite, increase the metabolic rate and increase physical activity. More fat means more leptin, which then causes the extra fat to be burned. The little glitch is that some people become resistant to leptin, so that their brain doesn't hear the fat tissue screaming that it's already full. Leptin resistance nearly always accompanies obesity, because it's a precondition of significant fat gain. If a person weren't leptin resistant, he wouldn't have the ability to gain more than a few pounds of fat without heroic overeating (which is very very unpleasant when your brain is telling you to stop). Animal models of leptin resistance develop something that resembles human metabolic syndrome (abdominal obesity, blood lipid abnormalities, insulin resistance, high blood pressure).

The Role of the Hypothalamus

The hypothalamus is on the underside of the brain connected to the pituitary gland. It's the main site of leptin action in the brain, and it controls the majority of leptin's effects on appetite, energy expenditure and insulin sensitivity. Most of the known gene variations that are associated with overweight in humans influence the function of the hypothalamus in some way (1). Not surprisingly, leptin resistance in the hypothalamus has been proposed as a cause of obesity. It's been shown in rats and mice that hypothalamic leptin resistance occurs in diet-induced obesity, and it's almost certainly the case in humans as well. What's causing leptin resistance in the hypothalamus?

There are three leading explanations at this point that are not mutually exclusive. One is cellular stress in the endoplasmic reticulum, a structure inside the cell that's used for protein synthesis and folding. I've read the most recent paper on this in detail, and I found it unconvincing (2). I'm open to the idea, but it needs more rigorous support.

A second explanation is inflammation in the hypothalamus. Inflammation inhibits leptin and insulin signaling in a variety of cell types. At least two studies have shown that diet-induced obesity in rodents leads to inflammation in the hypothalamus (3, 4)*. If leptin is getting to the hypothalamus, but the hypothalamus is insensitive to it, it will require more leptin to get the same signal, and fat mass will creep up until it reaches a higher setpoint.

The other possibility is that leptin simply isn't reaching the hypothalamus. The brain is a unique organ. It's enclosed by the blood-brain barrier (BBB), which greatly restricts what can enter and leave it. Both insulin and leptin are actively transported across the BBB. It's been known for a decade that obesity in rodents is associated with a lower rate of leptin transport across the BBB (5, 6).

What causes a decrease in leptin transport across the BBB? Triglycerides are a major factor. These are circulating fats going from the liver and the digestive tract to other tissues. They're one of the blood lipid measurements the doctor makes when he draws your blood. Several studies in rodents have shown that high triglycerides cause a reduction in leptin transport across the BBB, and reducing triglycerides allows greater leptin transport and fat loss (7, 8). In support of this theory, the triglyceride-reducing drug gemfibrozil also causes weight loss in humans (9)**. Guess what else reduces triglycerides and causes weight loss? Low-carbohydrate diets, and avoiding sugar and refined carbohydrates in particular.

In the next post, I'll get more specific about what factors could be causing hypothalamic inflammation and/or reduced leptin transport across the BBB. I'll also discuss some ideas on how to reduce leptin resistance sustainably through diet and exercise.


* This is accomplished by feeding them sad little pellets that look like greasy chalk. They're made up mostly of lard, soybean oil, casein, maltodextrin or cornstarch, sugar, vitamins and minerals (this is a link to the the most commonly used diet for inducing obesity in rodents). Food doesn't get any more refined than this stuff, and adding just about anything to it, from fiber to fruit extracts, makes it less damaging.

** Fibrates are PPAR agonists, so the weight loss could also be due to something besides the reduction in triglycerides.

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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.

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Palmitic Acid and Insulin Resistance: a New Paradigm

We've been having an interesting discussion in the comments about a recently published paper by Dr. Stephen C. Benoit and colleagues (free full text). They showed that a butter-rich diet causes weight gain and insulin resistance in rats, compared to a low-fat diet or a diet based on olive oil. They published a thorough description of the diets' compositions, which is very much appreciated!

They went on to show that infusing palmitic acid (a 16-carbon saturated fat) directly into the brain of rats also caused insulin resistance relative to oleic acid (an 18-carbon monounsaturated fat, like in olive oil). Here's a representation of palmitic acid. The COOH end is the acid end, and the squiggly line is the fatty end. Thus it's called a "fatty acid", various forms of which are the fat currency of the body.

One of the most interesting things about this study is the butter group that the investigators fed the same number of calories as the low-fat group (this is called pair-feeding). This group did not become overweight, and did not experience elevated fasting insulin and blood glucose relative to the low-fat group*. This shows clearly that the adverse effects of the butter diet were primarily due to the fact that rodents overeat when fed a high-fat diet.

Unfortunately, the paper doesn't provide longitudinal food intake data so we have no idea how many calories the rats in each group ate, beyond knowing that the low-fat group and the pair-fed butter group ate the same amount. We have no assurance that rats in the butter group and olive oil group ate the same number of calories over time. Rats eat less of foods they find bitter. This probably accounts, at least in part, for the beneficial effects of things like blueberry extracts on rodent models of disease. Olive oil may taste bitter to a rat, particularly when it's 20% of the diet by weight. Butter is tasty to calves, humans and rats alike.

Now we arrive at the speculative part of the post. I've been pondering a tough question for months. Palmitic acid has aroused universal ire for its supposed effects on lipid metabolism and insulin sensitivity**. But that leaves us with a puzzling paradox: palmitic acid is precisely the fatty acid that the liver produces when we eat carbohydrate. Our bodies contain the enzymes necessary to desaturate palmitic acid, making it monounsaturated. Why don't we use them? Why does the liver choose to secrete palmitic acid into the bloodstream unmodified? A fundamental metabolic process like this does not evolve by accident.

Here's the hypothesis. I believe that palmitic acid in the bloodstream does promote insulin resistance in rodents and probably humans as well. But there's a twist: it's probably not pathological at all; it's simply serving as a reversible signal to conserve blood glucose. This is similar to the hormone glucagon, which increases glucose production by the liver in response to falling blood glucose. Let's imagine an average person's eating habits throughout the day. Breakfast is at 8:00 am, lunch is at noon, and dinner is at 7:00 pm. The meals are about 45% carbohydrate, 40% fat and 15% protein. Let's imagine the fat consumed is animal fat, which contains some palmitic acid (25-30% of fatty acids).

The carbohydrate will be absorbed, partially turned into palmitic acid in the liver, and exported as VLDL particles. The amount of palmitic acid produced depends on the intake of starch and fructose, and will be relatively small except in the case of high carbohydrate or fructose consumption. Dietary fat will be absorbed in the intestine and sent out directly as chylomicrons (another lipoprotein particle). This is delayed relative to glucose absorption, such that the palmitic acid from both sources will enter the bloodstream at a similar time (peaks roughly 4 hours post-meal). Here is a hypothetical graph of blood glucose and blood palmitic acid at different points throughout this person's day (based on data such as these):
Notice a pattern? The concentrations of blood glucose and palmitic acid in the blood are approximately opposite one another. The brain responds to palmitic acid by temporarily decreasing the insulin sensitivity of other tissues, because it uses palmitic acid as a signal to begin conserving blood glucose while insulin is still elevated. Glucagon increases glucose secretion by the liver, and palmitic acid makes sure the glucose isn't removed from the bloodstream too quickly. I believe we're looking at a well-coordinated system designed by evolution to ensure that the glucose content of the blood remains stable after a meal.

There are two other scenarios in which this type of system would be advantageous. Let's imagine Nanook the Inuit has just killed a caribou in September. He eats some of the meat and organs with a generous slab of backfat. Large male caribou in the fall can carry a deposit of subcutaneous fat on their back that weighs up to 50 pounds. This fat is about 50% saturated, and roughly 25% palmitic acid. Here's a quote from the book My Life With the Eskimo, published by the anthropologist Vilhjalmur Stefansson in 1913:

The largest slab of back fat which I have seen taken from a Caribou on the Arctic coast was from a bull killed near Langton Bay early in September, the fat weighing 39 pounds. A large bull killed by Mr. Stefansson on Dease River in October had back fat 72 mm. in thickness (2 7/8 inches). Comparing the thickness of this with the Langton Bay specimen, the back fat of the Dease River bull must have weighed at least 50 pounds.

As the food is digested, Nanook's insulin rises to allow amino acids from the protein to be absorbed into his tissues from his bloodstream. But wait, insulin also tells tissues to absorb glucose, and the meal contained virtually no carbohydrate. Nanook is in danger of hypoglycemia. Fortunately, his brain detects the palmitic acid from the meal and signals his tissues to become resistant to the glucose-transporting effect of insulin. At the same time, glucagon signals the liver to release glucose into the bloodstream. His blood glucose remains stable.

The next week, the herd of caribou has moved on and there's no prey in Nanook's territory. He has to live on his own body fat for two days while he hunts. Fortunately, human body fat is about 20% palmitic acid. As fat is released into his bloodstream, the brain detects the palmitic acid and reduces peripheral insulin sensitivity. This helps Nanook's body conserve glucose and use his own body fat as fuel instead.

Over a wide range of fat, carbohydrate and calorie intakes, this system works to maintain stable blood glucose. These three scenarios all illustrate why palmitic acid would be helpful by causing temporary insulin resistance in situations where blood glucose needs to be conserved.

Back to the paper. The authors also showed that force-feeding rats large amounts of palmitic acid and calories (much more than would be present in animal fat) causes changes associated with insulin resistance in the brain. What I believe they have done is overstimulate this natural pathway for regulating insulin sensitivity by feeding unnatural amounts of palmitic acid.

Rats fed the butter diet at the same number of calories as the low-fat group did not exhibit metabolic dysfunction, showing that a reasonable amount of palmitic acid is compatible with metabolic health in this species. I believe this is even more true in humans, given our evolutionary history with animal fat and carbohydrate, both of which contribute palmitic acid to the circulation. Our deep-seated fear of saturated fat may have caused us to mistake a natural aspect of mammalian metabolism for a pathological process.


* The pair-fed butter group did show a lowered sensitivity to insulin, but given its normal weight, normal fasting insulin, and normal blood sugar, it really cannot be said to exhibit metabolic dysfunction in my opinion. Human "metabolic syndrome" involves overweight and elevated fasting insulin, which these rats did not have. Furthermore, the investigators did not show that the insulin sensitivity of the pair-fed butter group was different than a pair-fed olive oil group (they didn't make that comparison), so the finding doesn't implicate saturated fat specifically. Insulin sensitivity is determined in part by carbohydrate intake. This is normal. The more carbohydrate the body has to dispose of, the better it gets at handling it. On a high-fat diet, you don't need much insulin sensitivity to keep blood glucose in the normal range, because you aren't ingesting much glucose. On the other hand, in high-fat (low carbohydrate) diet trials on insulin-resistant people, insulin sensitivity often improves, however this is not the case in healthy insulin-sensitive people.

** The idea of palmitic acid's effect on insulin sensitivity is based largely on animal models and cell culture data. A long-term (rather than temporary and reversible) effect of palmitic acid on insulin sensitivity has never been convincingly demonstrated in humans, to my knowledge. After reviewing the literature, I've also concluded that a long-term, biologically significant effect of saturated fats in general on insulin sensitivity has not been convincingly demonstrated. I'll save that for another post.

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Paleolithic Diet Clinical Trials Part IV

Dr. Staffan Lindeberg has published a new study using the "paleolithic diet" to treat type II diabetics (free full text). Type II diabetes, formerly known as late-onset diabetes until it began appearing in children, is typically thought to develop as a result of insulin resistance (a lowered tissue response to the glucose-clearing function of insulin). This is often followed by a decrease in insulin secretion due to degeneration of the insulin-secreting pancreatic beta cells.

After Dr. Lindeberg's wild success treating patients with type II diabetes or glucose intolerance, in which he normalized the glucose tolerance of all 14 of his volunteers in 12 weeks, he set out to replicate the experiment. This time, he began with 13 men and women who had been diagnosed with type II diabetes for an average of 9 years.

Patients were put on two different diets for 3 months each. The first was a "conventional diabetes diet". I read a previous draft of the paper in which I believe they stated it was based on American Diabetes Association guidelines, but I can't find that statement in the final draft. In any case, here are the guidelines from the methods section:

The information on the Diabetes diet stated that it should aim at evenly distributed meals with increased intake of vegetables, root vegetables, dietary fiber, whole-grain bread and other whole-grain cereal products, fruits and berries, and decreased intake of total fat with more unsaturated fat. The majority of dietary energy should come from carbohydrates from foods naturally rich in carbohydrate and dietary fiber. The concepts of glycemic index and varied meals through meal planning by the Plate Model were explained [18]. Salt intake was recommended to be kept below 6 g per day.

The investigators gave the paleolithic group the following advice:

The information on the Paleolithic diet stated that it should be based on lean meat, fish, fruit, leafy and cruciferous vegetables, root vegetables, eggs and nuts, while excluding dairy products, cereal grains, beans, refined fats, sugar, candy, soft drinks, beer and extra addition of salt. The following items were recommended in limited amounts for the Paleolithic diet: eggs (≤2 per day), nuts (preferentially walnuts), dried fruit, potatoes (≤1 medium-sized per day), rapeseed or olive oil (≤1 tablespoon per day), wine (≤1 glass per day). The intake of other foods was not restricted and no advice was given with regard to proportions of food categories (e.g. animal versus plant foods). The evolutionary rationale for a Paleolithic diet and potential benefits were explained.

Neither diet was restricted in calories. After comparing the effects of the two diets for 3 months, the investigators concluded that the paleolithic diet:

• Reduced HbA1c more than the diabetes diet (a measure of average blood glucose)
• Reduced weight, BMI and waist circumference more than the diabetes diet
• Lowered blood pressure more than the diabetes diet
  
• Reduced triglycerides more than the diabetes diet
• Increased HDL more than the diabetes diet

However, the paleolithic diet was not a cure-all. At the end of the trial, 8 out of 13 patents still had diabetic blood glucose after an oral glucose tolerance test (OGTT). This is compared to 9 out of 13 for the diabetes diet. Still, 5 out of 13 with "normal" OGTT after the paleolithic diet isn't bad. The paleolithic diet also significantly reduced insulin resistance and increased glucose tolerance, although it didn't do so more than the diabetes diet.

As has been reported in other studies, paleolithic dieters ate fewer total calories than the comparison group. This is part of the reason why I believe that something in the modern diet causes hyperphagia, or excessive eating. According to the paleolithic diet studies, this food or combination of foods is neolithic, and probably resides in grains, refined sugar and/or dairy. I have my money on wheat and sugar, with a probable long-term contribution from industrial vegetable oils as well.

Were the improvements on the paleolithic diet simply due to calorie restriction? Maybe, but keep in mind that neither group was told to restrict its caloric intake. The reduction in caloric intake occurred naturally, despite the participants presumably eating to fullness. I suspect that the paleolithic diet reset the dieters' body fat set-point, after which fat began pouring out of their fat tissue. They were supplementing their diets with body fat-- 13 pounds (6 kg) of it over 3 months.

The other notable difference between the two diets, besides food types, was carbohydrate intake. The diabetes diet group ate 56% more carbohydrate than the paleo diet group, with 42% of their calories coming from it. The paleolithic group ate 32% carbohydrate. Could this have been the reason for the better outcome of the paleolithic group? I'd be surprised if it wasn't a factor. Advising a diabetic to eat a high-carbohydrate diet is like asking someone who's allergic to bee stings to fetch you some honey from your bee hive. Diabetes is a disorder of glucose intolerance. Starch is a glucose polymer.

Although to be fair, participants on the diabetes diet did improve in a number of ways. There's something to be said for eating whole foods.

This trial was actually a bit of a disappointment for me. I was hoping for a slam dunk, similar to Lindeberg's previous study that "cured" all 14 patients of glucose intolerance in 3 months. In the current study, the paleolithic diet left 8 out of 13 patients diabetic after 3 months. What was the difference? For one thing, the patients in this study had well-established diabetes with an average duration of 9 years. As Jenny Ruhl explains in her book Blood Sugar 101, type II diabetes often progresses to beta cell loss, after which the pancreas can no longer secrete an adequate amount of insulin.

This may be the critical finding of Dr. Lindeberg's two studies: type II diabetes can be prevented when it's caught at an early stage, such as pre-diabetes, whereas prolonged diabetes may cause damage that cannot be completely reversed though diet. I think this is consistent with the experience of many diabetics who have seen an improvement but not a cure from changes in diet. Please add any relevant experiences to the comments.

Collectively, the evidence from clinical trials on the "paleolithic diet" indicate that it's a very effective treatment for modern metabolic dysfunction, including excess body fat, insulin resistance and glucose intolerance. Another way of saying this is that the modern industrial diet causes metabolic dysfunction.

Paleolithic Diet Clinical Trials
Paleolithic Diet Clinical Trials Part II
One Last Thought
Paleolithic Diet Clinical Trials Part III

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Letter to the Editor

I just got a letter to the editor published in the journal Obesity. It's a comment on an article published in October titled "Efficiency of Intermittent Exercise on Adiposity and Fatty Liver in Rats Fed With High-fat Diet."

In the study, they placed rats on a diet composed of "commercial rat chow plus peanuts, milk chocolate, and sweet biscuit in a proportion of 3:2:2:1," and then proceeded to simply call it a "high-fat diet" in the title and text body, with no reference to its actual composition outside the methods section. We can't tolerate this kind of fudging if we want real answers from nutrition science. Rats eating the "high-fat diet" developed abdominal obesity, fatty liver and hyperphagia, but this was attenuated by exercise.

As I like to say, the problem isn't usually in the data, it's in the interpretation of the data. The result is interesting and highly relevant. But you can't use terminology that tars and feathers all fat when your diet was in fact high in linoleic acid (omega-6), low in omega-3 and high in sugar and refined grains. Especially when butter and coconut oil don't cause the same pathology. I pointed out in the letter that we need to be more precise about how we define "high-fat diets". I also pointed out that the study is highly relevant to the modern U.S., because it supports the hypothesis that a junk food diet high in linoleic acid and sugar causes metabolic disturbances and fatty liver, and exercise may be protective.

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