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.

Krauss's New Article on Saturated Fat Intervention Trials

Dr. Ronald Krauss's group just published another article in the American Journal of Clinical Nutrition, this time on the intervention trials examining the effectiveness of reducing saturated fat and/or replacing it with other nutrients, particularly carbohydrate or polyunsaturated seed oils. I don't agree with everything in this article. For example, they cite the Finnish Mental Hospital trial. They openly acknowledge some contradictory data, although they left out the Sydney diet-heart study and the Rose et al. corn oil study, both of which showed greatly increased mortality from replacing animal fats with polyunsaturated seed oils. Nevertheless, they get it right in the end:

Particularly given the differential effects of dietary saturated fats and carbohydrates on concentrations of larger and smaller LDL particles, respectively, dietary efforts to improve the increasing burden of CVD risk associated with atherogenic dyslipidemia should primarily emphasize the limitation of refined carbohydrate intakes and a reduction in excess adiposity.

This is really cool. Krauss is channeling Weston Price. If this keeps up, I may have no reason to blog anymore!

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.

New Saturated Fat Review Article by Dr. Ronald Krauss

I never thought I'd see the day when one of the most prominent lipid researchers in the world did an honest review of the observational studies evaluating the link between saturated fat and cardiovascular disease. Dr. Ronald Krauss's group has published a review article titled "Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease". As anyone with two eyes and access to the medical literature would conclude (including myself), they found no association whatsoever between saturated fat intake and heart disease or stroke:

A meta-analysis of prospective epidemiologic studies showed that there is no significant evidence for concluding that dietary saturated fat is associated with an increased risk of CHD or CVD.

Bravo, Dr. Krauss. That was a brave move.

Thanks to Peter for pointing out this article.

Paleo is Going Mainstream

There was an article on the modern "Paleolithic" lifestyle in the New York Times today. I thought it was a pretty fair treatment of the subject, although it did paint it as more macho and carnivorous than it needs to be. It features three attractive NY cave people. It appeared in the styles section here. Paleo is going mainstream. We can expect media health authorities to start getting defensive about it any minute now.