High-Fat Diets, Obesity and Brain Damage

Many of you have probably heard the news this week:

High-fat diet may damage the brain
Eating a high-fat diet may rapidly injure brain cells
High fat diet injures the brain
Brain injury from high-fat foods

Your brain cells are exploding with every bite of butter!  Just kidding.  The study in question is titled "Obesity is Associated with Hypothalamic Injury in Rodents and Humans", by Dr. Josh Thaler and colleagues, with my mentor Dr. Mike Schwartz as senior author (1).  We collaborated with the labs of Drs. Tamas Horvath and Matthias Tschop.  I'm fourth author on the paper, so let me explain what we found and why it's important.  

The Questions

Among the many questions that interest obesity researchers, two stand out:

1. What causes obesity?
2. Once obesity is established, why is it so difficult to treat?

Our study expands on the efforts of many other labs to answer the first question, and takes a stab at the second one as well.  Dr. Licio Velloso and collaborators were the first to show in 2005 that inflammation in a part of the brain called the hypothalamus contributes to the development of obesity in rodents (2), and this has been independently confirmed several times since then.  The hypothalamus is an important brain region for the regulation of body fatness, and inflammation keeps it from doing its job correctly.

The Findings

Inflammation occurs in many tissues when rodents are placed on a fattening diet, but this usually takes weeks or months to develop, and therefore it is often considered secondary to the development of obesity.  One of the things we were able to show in this study is that in rodents, we can detect signs of inflammation in the hypothalamus within one day of exposure to a fattening diet, making it the earliest known inflammatory event during the development of obesity.  This is consistent with the idea that dysfunction of other tissues is the result, at least partially, of dysfunction that occurs first in the brain.

Our study also addresses the second question: why is obesity so difficult to treat?  We know that brain inflammation contributes to obesity in rodents, so one possibility is that the hypothalamus sustains damage during this process, which durably elevates the "setpoint" around which body fat mass is defended by the body.  In other words, damage to the part of the brain that regulates body fatness makes the body "want" to carry more fat and resist fat loss attempts.

This is the hypothesis we began to test in this study, and we found evidence that supports it.  Rodents placed on a fattening diet show evidence of neuron injury in as little as three days.  Our study was not able to say that neuron injury causes obesity or resistance to fat loss, only that obesity and neuron injury are associated with one another.  This is the first step in this line of investigation, and we are currently following up with related studies that will expand the findings. 

The most striking finding in the paper was contributed by our collaborator Dr. Ellen Schur, who showed by MRI that obesity is associated with a marker of neuron injury in the hypothalamus of live humans. As you might imagine, this increased the impact of the study considerably!  It is important to point out that we found the suggestion of neuron injury specifically in the hypothalamus, not in other brain regions.  We did not find changes in brain regions responsible for thought, language, movement, etc., that might be expected to impact a person's ability to think and function.

The Diet

The "high-fat diet" that was used in this study is Research Diets D12492 (3), and the comparison diet was normal unpurified rodent chow.  Normal rodent chow is a whole food based pellet that is mostly composed of unrefined corn, soybeans, a small amount of meat and animal fat, and added micronutrients.  It is very low in fat, typically ~14 percent of calories.  They do just fine on this food, particularly if they are given a running wheel and other forms of environmental enrichment. 

D12492 is a "purified" diet that is fundamentally different from unrefined rodent chow.  It is one of the many rodent diets that were created because investigators needed a highly consistent food to minimize experimental variability.  Whereas unrefined chow can have a different composition based on the variety of corn/soybeans used, the terroir, the particular growing conditions of that year, etc., purified diets are composed entirely of highly refined ingredients so they are much less variable.  However, it rapidly became clear that rodents don't do as well on these diets, even if macronutrients and micronutrients are approximately matched to the unrefined chow diets.  D12492 is composed of non-hydrogenated lard, soybean oil, maltodextrin, sucrose, casein for protein, cellulose for fiber, and added vitamins and minerals.  It does contain sugar, but the amount is modest (6.8 percent of calories).

D12492 is 60 percent fat by calories.  Although rodents love the taste of it, it is not good for their health-- susceptible strains of rats and mice will begin gaining fat in as little as a week on the diet, become morbidly obese by three months, sometimes develop diabetes, and live less than half a typical rodent lifespan if they are allowed to age (generally they are not). Personally, I refer to this diet as a "purified high-fat diet", because that acknowledges that not only is it high in fat, it is also composed of refined ingredients.  In our study, there is no way for us to know if what we observed in rodents was due to the dietary fat per se, some other aspect of the diet, or both.  Based on other findings, I strongly suspect that it is both.

We deliberately use rodent strains that are susceptible to obesity on this diet.  Some strains are more resistant to obesity than others, but a comprehensive look at the literature reveals that high-fat diets are generally not good for rodents, and most strains tend to gain some amount of fat and develop long-term health problems on high-fat feed.  There are a few exceptions in the literature if you look hard enough for them, but they are drowned out by the much greater number of studies showing harm.

So if we're deliberately selecting rodent strains that are particularly sensitive to fat gain on a purified high-fat diet, how can we generalize from this and say that dietary fat causes damage in the brain and obesity?  The answer is that we can't, and we haven't.   Nowhere in the paper does it say that dietary fat per se causes damage to the brain, or even causes obesity, and Drs. Thaler and Schwartz were careful not to say that in interviews either.  We choose rodent strains that are susceptible to obesity on purified high-fat diets simply because we're studying obesity, and we know that feeding this diet to the right strains of rats and mice produces it readily.  

The fact is, we don't know what aspects of D12492 cause injury to neurons and obesity in rodents, and we don't know if those are the same factors that cause obesity in humans.  That was not the point of the study!  The point was to try to understand what's happening in the brain during the development of obesity.  Based on previous studies, the dietary fat itself is probably an important component that makes D12492 fattening in rodents, but whether high dietary fat would lead to obesity in the context of a well-composed whole food-based high fat diet, and a running wheel, is not known. 

The Implications

This study once again highlights the importance of the brain in the development of obesity, and shows directly for the first time that similar changes occur in humans.  Our findings also raise the possibility that injury to the hypothalamus may contribute to the fact that obesity is so difficult to durably reverse.  That does not mean that fat loss efforts are hopeless!  I believe that with the right techniques, many obese people can lose a substantial amount of fat and keep it off.  But realistically, we already know that it is rare for a long-term obese person to attain a totally lean state.  Persistent changes in the function of the hypothalamus are a logical way to explain this, although more research will be required before we can say it conclusively. 

I do not think this study suggests that dietary fat is inherently fattening or causes damage to neurons in humans.  The question of whether or not dietary fat is inherently fattening is controversial, but our study did not address it.  Based on my reading, studies show overall that dietary fat is not fattening in humans as long as total calorie intake remains appropriate.  However, adding fat to food that is otherwise low in fat does facilitate overconsumption of calories in some people, by increasing energy density and food palatability/reward, and this has been demonstrated many times.  I think the fact that low-carbohydrate diets cause fat loss in many obese people offers support to the idea that dietary fat is not inherently fattening in humans. 

This was not a diet study, but if there is a dietary message in it, it is this: eat a whole food based diet that allows you to reach or maintain a healthy weight naturally.