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.

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.

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.

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

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.

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.

U.S. Weight, Lifestyle and Diet Trends, 1970- 2007

For this post, I compiled statistics on U.S. weight, health and lifestyle trends, and graphed them as consistently as possible. They span the period from 1970 to 2007, during which the obesity rate doubled. The data come from the National Health and Nutrition Examination Survey (NHANES), the Behavioral Risk Factor Surveillance System (BRFSS), and the U.S. Department of Agriculture (USDA). Some of the graphs are incomplete, either because the data don't exist, or because I wasn't able to find them. Obesity is defined as a body mass index (BMI) of 30+; overweight is a BMI of 25+. Yes, it's frightening. It has affected adults and children (NHANES).
The percentage of Americans who report exercising in their spare time has actually increased since 1988 (BRFSS).
We're eating about 250 more calories per day, according to NHANES.
The 250 extra calories are coming from carbohydrate (NHANES).

We're eating more vegetables and fruit (USDA).
We're eating more meat by weight, although calories from meat have probably gone down because the meat has gotten leaner (USDA). This graph represents red meat, fish and poultry. The increase comes mostly from poultry. Boneless, skinless chicken breasts anyone?
We're eating more sugar (USDA). The scale of the graph doesn't allow you to fully appreciate that sweetener consumption had increased by a full 100 calories per day by 1999, although it has dropped a bit since then. This is based on food disappearance data. In other words, the amount consumed is estimated using the amount sold domestically, minus a percentage that approximates waste. High-fructose corn syrup has seized nearly 50% of the sweetener market since 1970.
Again, the scale of the graph doesn't allow you to fully appreciate the magnitude of the change here. In 2000, we ate approximately 2.5 ounces, or 280 calories, more processed grains per day than in 1970 (USDA). That has since decreased slightly (34 calories). You might be saying to yourself right now "hey, that plus the 100 calories from sugar adds up to more of an increase than the NHANES data show!" Yes, and I think that points to the fact that the data sets are not directly comparable. NHANES data are self-reported whereas USDA data are collected from vendors. Regardless of the absolute numbers, our processed grain consumption has gone way up since 1970.

Wheat is still king. Although we grow a lot of corn in this country, most of it gets fed to animals. We prefer eating wheat without first feeding it to an intermediary. In absolute quantity, wheat consumption has increased more than any other grain (not including corn syrup).
Bye bye whole milk. Hello skim milk (USDA).

This graph represents "added fats", as opposed to fats that occur naturally in meat or milk (the USDA does not track the latter). Added fats include salad oil, cooking oil, deep fry oil, butter, lard, tallow, etc. We are eating a lot more vegetable oil than we were in 1970. It comes chiefly from the industrial, omega-6 rich oils such as soybean, corn and canola. Added animal fats have increased slightly, but it's pretty insignificant in terms of calories.

There is an artifact in this graph that I have to point out. In 2000, the USDA changed the way it gathered vegetable oil data. This led to an abrupt, apparent increase in its consumption that is obvious on the graph. So it's difficult to make any quantitative conclusions, but I think it's clear nevertheless that vegetable oil intake has increased considerably.

Between 1970 and 1980, something changed in the U.S. that caused a massive increase in obesity and other health problems. Some combination of factors reached a critical mass that our metabolism could no longer tolerate. The three biggest changes in the American diet since 1970:

• An increase in cereal grain consumption, particularly wheat.
• An increase in sweetener consumption
• The replacement of meat and milk fat with industrial vegetable oils, with total fat intake remaining the same.

Mainstream America has done to itself what it did to native American and other indigenous cultures worldwide, with the same result.

Paleolithic Diet Clinical Trials Part II

There were a number of remarkable changes in both trials. I'll focus mostly on Dr. Lindeberg's trial because it was longer and better designed. The first thing I noticed is that caloric intake dropped dramatically in both trials, -36% in the first trial and a large but undetermined amount in Dr Lindeberg's. The Mediterranean diet group ended up eating 1,795 calories per day, while the paleolithic dieters ate 1,344. In both studies, participants were allowed to eat as much as they wanted, so those reductions were purely voluntary.

This again agrees with the theory that certain grains (wheat) promote hyperphagia, or excessive eating. It's the same thing you see in low-carbohydrate diet trials, such as this one, which also reduce grain intake. The participants in Lindeberg's study were borderline obese. When you're overweight and your body resets its fat mass set-point due to an improved diet, fatty acids come pouring out of fat tissue and you don't need as many calories to feel satisfied. Your diet is supplemented by generous quantities of lard. Your brain decreases your calorie intake until you approach your new set-point.

That's what I believe happened here. The paleolithic group supplemented their diet with 3.9 kg of their own rump fat over the course of 12 weeks, coming out to 30,000 additional calories, or 357 calories a day. Not quite so spartan when you think about it like that.

The most remarkable thing about Lindeberg's trial was the fact that the 14 people in the paleolithic group, 2 of which had moderately elevated fasting blood glucose and 10 of which had diabetic fasting glucose, all ended up with normal fasting glucose after 12 weeks. That is truly amazing. The mediterranean diet worked also, but only in half as many participants.

If you look at their glucose tolerance by an oral glocose tolerance test (OGTT), the paleolithic diet group improved dramatically. Their rise in blood sugar after the OGTT (fasting BG subtracted out) was 76% less at 2 hours. If you look at the graph, they were basically back to fasting glucose levels at 2 hours, whereas before the trial they had only dropped slightly from the peak at that timepoint. The mediterranean diet group saw no significant improvement in fasting blood glucose or the OGTT. Lindeberg is pretty modest about this finding, but he essentially cured type II diabetes and glucose intolerance in 100% of the paleolithic group.

Fasting insulin, the insulin response to the OGTT and insulin sensitivity improved in the paleolithic diet whereas only insulin sensitivity improved significantly in the Mediterranean diet. Fasting insulin didn't decrease as much as I would have thought, only 16% in the paleolithic group.

Another interesting thing is that the paleolithic group lost more belly fat than the Mediterranean group, as judged by waist circumference. This is the most dangerous type of fat, which is associated with, and contributes to, insulin resistance and the metabolic syndrome. Guess what food belly fat was associated with when they analyzed the data? The strongest association was with grain consumption (probably mostly wheat), and the association remained even after adjusting for carbohydrate intake. In other words, the carbohydrate content of grains does not explain their association with belly fat because "paleo carbs" didn't associate with it. The effect of the paleolithic diet on glucose tolerance was also not related to carbohydrate intake.

So in summary, the "Mediterranean diet" may be healthier than a typical Swedish diet, while a diet loosely modeled after a paleolithic diet kicks both of their butts around the block. My opinion is that it's probably due to eliminating wheat, substantially reducing refined vegetable oils and dumping the processed junk in favor of real, whole foods. Here's a zinger from the end of the paper that sums it up nicely (emphasis mine):

The larger improvement of glucose tolerance in the Paleolithic group was independent of energy intake and macronutrient composition, which suggests that avoiding Western foods is more important than counting calories, fat, carbohydrate or protein. The study adds to the notion that healthy diets based on whole-grain cereals and low-fat dairy products are only the second best choice in the prevention and treatment of type 2 diabetes.

Paleolithic Diet Clinical Trials

If Dr. Ancel Keys (of diet-heart hypothesis fame) had been a proponent of "paleolithic nutrition", we would have numerous large intervention trials by now either confirming or denying its ability to prevent health problems. In this alternate reality, public health would probably be a lot better than it is today. Sadly, we have to settle for our current reality where the paleolithic diet has only been evaluated in two small trials, and medical research spends its (our) money repeatedly conducting failed attempts to link saturated fat to every ill you can think of. But let's at least take a look at what we have.

Both trials were conducted in Sweden. In the first one, lead by Dr. Per Wändell, 14 healthy participants (5 men, 9 women) completed a 3-week dietary intervention in which they were counseled to eat a "paleolithic diet". Calories were not restricted, only food categories were. Participants were told to eat as much as they wanted of fruit, vegetables, fish, lean meats, nuts, flax and canola oil, coffe and tea (without dairy). They were allowed restricted quantities of dried fruit, potatoes (2 medium/day) salted meat and fish, fat meat and honey. They were told not to eat dairy, grain products, canned food, sugar and salt.

After three weeks, the participants had:

• Decreased their caloric intake from 2,478 to 1,584 kcal
• Increased their percentage protein and fat, while decreasing carbohydrate
• Decreased saturated fat, increased dietary cholesterol, decreased sodium intake, increased potassium
  
• Lost 2.3 kg (5 lb)
• Decreased waist circumference, blood pressure and PAI-1

Not bad for a 3-week intervention on healthy subjects. This study suffered from some serious problems, however. #1 is the lack of a control group as a means for comparison. Ouch. #2 is the small study size and resulting lack of statistical power. I consider this one encouraging but by no means conclusive.

The second study was conducted by the author of the Kitava study, Dr. Staffan Lindeberg. The study design was very interesting. He randomly assigned 29 men with ischemic heart disease, plus type II diabetes or glucose intolerance, to either a "Mediterranean diet" or a "paleolithic diet". Neither diet was calorie-restricted. Here's the beauty of the study design: the Mediterranean diet was the control for the paleo diet. The reason that's so great is it completely eliminates the placebo effect. Both groups were told they were being assigned to a healthy diet to try to improve their health. Each group was educated on the health benefits of their diet but not the other one. It would have been nice to see a regular non-intervention control group as well, but this design was adequate to see some differences.

Participants eating the Mediterranean diet were counseled to focus on whole grains, low-fat dairy, potatoes, legumes, vegetables, fruit, fatty fish and vegetable oils rich in monounsaturated fats and alpha-linolenic acid (omega-3). I'm going to go on a little tangent here. This is truly a bizarre concept of what people eat in the Mediterranean region. It's a fantasy invented in the US to justify the mainstream concept of a healthy diet. My father is French and I spent many summers with my family in southern France. They ate white bread, full-fat dairy at every meal, legumes only if they were smothered in fatty pork, sausages and lamb chops. In fact, full-fat dairy wasn't fat enough sometimes. Many of the yogurts and cheeses we ate were made from milk with extra cream added. Want to get a lecture from Grandmere? Try cutting the fat off your pork chop!

The paleolithic group was counseled to eat lean meat, fish, fruit, leafy and cruciferous vegetables, root vegetables (including moderate amounts of potatoes), eggs and nuts. They were told to avoid dairy, grain products, processed food, sugar and beer.

Both groups were bordering on obese at the beginning of the study. All participants had cardiovascular disease and moderate to severe glucose intolerance (i.e. type II diabetes). After 12 weeks, both groups improved on several parameters. That includes fat mass and waist circumference. But the paleolithic diet trumped the Mediterranean diet in many ways:

• Greater fat loss in the the midsection and a trend toward greater weight loss
  
• Greater voluntary reduction in caloric intake (total intake paleo= 1,344 kcal; Med= 1,795)
  
• A remarkable improvement in glucose tolerance that did not occur significantly in the Mediterranean group
• A decrease in fasting glucose
  
• An increase in insulin sensitivity (HOMA-IR)
  

Overall, the paleolithic diet came out looking very good. But I haven't even gotten to the best part yet. At the beginning of the trial, 12 out of the 14 people in the paleo group had elevated fasting glucose. At the end, every single one had normal fasting glucose. In the Mediterranean group, 13 out of 15 began with elevated glucose and 8 out of 15 ended with it. This clearly shows that a paleolithic diet is an excellent way to restore glucose control to a person who still has beta cells in their pancreas.

This post is getting long, so I think I'll save the interpretation for the next post.

Rats on Junk Food

If diet composition causes hyperphagia, we should be able to see it in animals. I just came across a great study from the lab of Dr. Neil Stickland that explored this in rats. They took two groups of pregnant rats and fed them two different diets ad libitum, meaning the rats could eat as much as they wanted. Here's what the diets looked like:

The animals were fed two types of diet throughout the study. They were fed either RM3 rodent chow alone ad libitum (SDS Ltd, Betchworth, Surrey, UK) or with a junk food diet, also known as cafeteria diet, which consisted of eight different types of palatable foods, purchased from a British supermarket. The palatable food included biscuits, marshmallows, cheese, jam doughnuts, chocolate chip muffins, butter flapjacks, potato crisps and caramel/chocolate bars.

It's important to note that the junk food-fed rats had access to rat chow as well. Now here's where it gets interesting. Rats with access to junk food in addition to rat chow ate 56% more calories than the chow-only group! Here's what they had to say about it:

These results clearly show that pregnant rats, given ad libitum access to junk food, exhibited hyperphagia characterised by a marked preference for foods rich in fat, sucrose and salt at the expense of protein-rich foods, when compared with rats that only had access to rodent chow. Although the body mass of dams was comparable among all groups at the start of the experiment, the increased energy intake in the junk food group throughout gestation was accompanied by an increase in body mass at G20 [gestational day 20] with the junk food-fed dams being 13 % heavier than those fed chow alone.

Hmm, this is remarkably reminiscent of what's happening to a certain group of humans in North America right now: give them access to food made mostly of refined grains, sugar, and industrially processed vegetable oil. They will prefer it to healthier food, to the point of overeating. The junk food then drives hyperphagia by interfering with the body's feedback loops that normally keep feeding behaviors and body fat within the optimal range. These data support the hypothesis that metabolic damage is the cause of, not the result of, "super-sized" food portions and other similar cultural phenomena.

The rest of the paper is interesting as well. Pups born to mothers who ate junk food while pregnant and lactating had a greater tendency to eat junk than pups born to mothers who ate rat chow during the same period. This underscores the idea that poor nutrition can set a child up for a lifetime of problems.

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.

New Low-carb Study

I know you’ve all heard the news about the new low-carb study in the New England Journal of Medicine by now, but I have to chime in. I‘m going to try to offer you a different perspective of the study that you may not have found elsewhere. First of all, this is a Rolls Royce of a study. It was large, well-controlled, and two years long. It was partly funded by the Atkins foundation, but it's a peer-reviewed study in a good journal and if anything the study design is slanted against the low-carbohydrate diet.

The study compared the weights and various health parameters of 322 overweight subjects put on one of three diets: a “low-fat diet”, a Mediterranean diet and a “low-carbohydrate diet”. The first two were calorie-restricted while the low-carb diet was not. First of all, the “low-fat” diet was not particularly low in fat. It was 30% fat by calories, only a few percent short of the US average. What they call low-fat in the study is actually a calorie-restricted version of the American Heart Association diet recommendation, which suggests:

“…30% of calories from fat, 10% calories from saturated fat, and an intake of 300 mg of cholesterol per day. The Participants were counseled to consume low-fat grains, vegetables, fruits, and legumes and to limit their consumption of additional fats, sweets and high-fat snacks.”

So henceforth, I’ll refer to it as the AHA diet rather than the low-fat diet.

The “low-carb” diet wasn’t particularly low in carbohydrate either. The low-carb group was only getting 10% fewer calories from carbohydrate than the low-fat or Mediterranean diet groups. Despite these problems, the low-carbohydrate diet was the most effective overall. It caused a weight loss of 5.5 kg (12 lb), compared to 4.6 kg (10 lb) and 3.3 kg (7.4 lb) for the Mediterranean and AHA diets, respectively.

One of the most amazing aspects of the study is that the low-carb diet was the only one that wasn’t calorie-restricted, yet it caused the most weight loss. People in the low-carb group naturally reduced their calorie intake over the course of the study, ending up with an intake similar to the AHA group.

The low-carb diet also came out on top in most of the markers of health they examined. It caused the largest drop in HbA1c, a measure of average blood glucose level. It caused the largest drop in C-reactive protein, a measure of inflammation (the Mediterranean diet also did well). And finally, it caused the biggest improvement in the triglyceride:HDL ratio. This ratio is the best blood lipid predictor of heart disease risk I’m aware of in modern Western populations. The lower, the better. They didn't calculate it in the study so I had to do it myself. Here's a graph of the change in trig:HDL ratio for each group over the course of the study:


Other interesting findings: despite the calorie restriction, diabetic participants on the AHA group actually saw a significant increase in fasting blood glucose.

I've speculated before that wheat and sugar may cause hyperphagia, or excessive eating. We can see from these results that reducing carbohydrate (and probably wheat) reduces overall caloric intake quite significantly. This squares with the findings of the recent Chinese study that showed an increase in calorie intake and weight, correlating with the replacement of rice with wheat as the primary carbohydrate. It also squares with diet trends in the US, where wheat consumption has risen alongside calorie intake and weight.

I'd love to know what the results would have looked like if they had gone on a true low-carbohydrate diet, or even simply eliminated grains and sugar.

Another China Tidbit

A final note about the Chinese study in the previous post: the overweight vegetable-eaters (read: wheat eaters) exercised more than their non-vegetable-eating, thin neighbors. So although their average calorie intake was a bit higher, their expenditure was as well. So much for 'calories in, calories out'...

Although I speculated in the last post that affluent people might be eating more wheat and fresh vegetables, the data don't support that. Participants with the highest income level actually adhered to the wheat and vegetable-rich pattern the least, while low-income participants were most likely to eat this way.

Interestingly, education showed a (weaker) trend in the opposite direction. More educated participants were more likely to eat the wheat-vegetable pattern, while the opposite was true of less educated participants. Thus, it looks like wheat makes people more educated. Just kidding, that's exactly the logic we have to avoid when interpreting this type of study!

Wheat is Invading China

Dr. Michael Eades linked to an interesting study yesterday on his Health and Nutrition blog. It's entitled "Vegetable-Rich Food Pattern is Related to Obesity in China."

It's one of these epidemiological studies where they try to divide subjects into different categories of eating patterns and see how health problems associate with each one. They identified four patterns: the 'macho' diet high in meat and alcohol; the 'traditional' diet high in rice and vegetables; the 'sweet tooth' pattern high in cake, dairy and various drinks; and the 'vegetable rich' diet high in wheat, vegetables, fruit and tofu. The only pattern that associated with obesity was the vegetable-rich diet. The 25% of people eating closest to the vegetable-rich pattern were more than twice as likely to be obese as the 25% adhering the least.

The authors of the paper try to blame the increased obesity on a higher intake of vegetable oil from stir-frying the vegetables, but that explanation is juvenile and misleading. A cursory glance at table 3 reveals that the vegetable-eaters weren't eating any more fat than their thinner neighbors. Dr. Eades suggests that their higher carbohydrate intake (+10%) and higher calorie intake (+120 kcal/day) are responsible for the weight gain, but I wasn't satisfied with that explanation so I took a closer look.

One of the most striking elements of the 'vegetable-rich' food pattern is its replacement of rice with wheat flour. The 25% of the study population that adhered the least to the vegetable-rich food pattern ate 7.3 times more rice than wheat, whereas the 25% sticking most closely to the vegetable-rich pattern ate 1.2 times more wheat than rice! In other words, wheat flour had replaced rice as their single largest source of calories. This association was much stronger than the increase in vegetable consumption itself!

All of a sudden, the data make perfect sense. Wheat seems to destroy the metabolism of cultures wherever it goes. I think the reason we don't see the same type of association in American epidemiological studies is that everyone eats wheat. Only in a culture that has a true diversity of diet can you find a robust association like this. The replacement of rice with wheat may have caused the increase in calorie intake as well, subsequent to metabolic dysfunction. Clinical trials of low-carbohydrate diets as well as 'paleolithic diets' have shown good metabolic outcomes from wheat avoidance, although one can't be sure that wheat is the only culprit from those data.

I don't think the vegetables had anything to do with the weight gain, they were just incidentally associated with wheat consumption. But I do think these data argue against the commonly-held idea that vegetables protect against overweight.