Obesity and the Brain

Nature Genetics just published a paper that caught my interest (1). Investigators reviewed the studies that have attempted to determine associations between genetic variants and common obesity (as judged by body mass index or BMI). In other words, they looked for "genes" that are suspected to make people fat.

There are a number of gene variants that associate with an increased or decreased risk of obesity. These fall into two categories: rare single-gene mutations that cause dramatic obesity, and common variants that are estimated to have a very small impact on body fatness. The former category cannot account for common obesity because it is far too rare, and the latter probably cannot account for it either because it has too little impact*. Genetics can't explain the fact that there were half as many obese people in the US 40 years ago. Here's a wise quote from the obesity researcher Dr. David L. Katz, quoted from an interview about the study (2):

Let us by all means study our genes, and their associations with our various shapes and sizes... But let's not let it distract us from the fact that our genes have not changed to account for the modern advent of epidemic obesity -- our environments and lifestyles have.

Exactly. So I don't usually pay much attention to "obesity genes", although I do think genetics contributes to how a body reacts to an unnatural diet/lifestyle. However, the first part of his statement is important too. Studying these types of associations can give us insights into the biological mechanisms of obesity when we ask the question "what do these genes do?" The processes these genes participate in should be the same processes that are most important in regulating fat mass.

So, what do the genes do? Of those that have a known function, nearly all of them act in the brain, and most act in known body fat regulation circuits in the hypothalamus (a brain region). The brain is the master regulator of body fat mass. It's also the master regulator of nearly all large-scale homeostatic systems in the body, including the endocrine (hormone) system. Now you know why I study the neurobiology of obesity.


* The authors estimated that "together, the 32 confirmed BMI loci explained 1.45% of the inter-individual variation in BMI." In other words, even if you were unlucky enough to inherit the 'fat' version of all 32 genes, which is exceedingly unlikely, you would only have a slightly higher risk of obesity than the general population.

Two Things that Get on My Nerves, Part I

The "Thrifty Gene" Hypothesis

The thrifty gene hypothesis is the darling of many obesity researchers. It was proposed in 1962 by the geneticist James V. Neel to explain the high rates of obesity in modern populations, particularly modernizing American Indians. It states that our species evolved under conditions of frequent starvation, so we're designed to store every available calorie. In today's world of food abundance, our bodies continue to be thrifty and that's why we're fat.

Obesity researchers love it because it dovetails nicely with the equally dim "calories-in, calories-out hypothesis", whereby calories alone determine body composition. You practically can't read a paper on overweight without seeing an obligatory nod to the thrifty gene hypothesis. The only problem is, it's wrong.

The assumption that hunter-gatherers and non-industrial agriculturalists lived under chronic calorie deprivation has been proven false. The anthropological evidence indicates that most hunter-gatherers had abundant food, most of the time. They did have fluctuations in energy balance, but the majority of the time they had access to more calories than they needed, just like us. Yet they were not fat.

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

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

Here's what Neel had to say about his own theory in 1982 (excerpts from Good Calories, Bad Calories):

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

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

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

RIP, thrifty gene.


For more information on bodyweight regulation, see:

Insulin Controls Your Fat
Leptin and Lectins
Thoughts on Obesity Part I
Thoughts on Obesity Part II
Body Composition

Masai and Atherosclerosis

I've been digging deeper into the health of the Masai lately. A commenter on Chris's blog pointed me to a 1972 paper showing that the Masai have atherosclerosis, or hardening of the arteries. This interested me so I got my hands on the full text, along with a few others from the same time period. What I found is nothing short of fascinating.

First, some background. Traditional Masai in Kenya and Tanzania are pastoralists, subsisting on fermented cow's milk, meat and blood, as well as traded food in modern times. They rarely eat fresh vegetables. Contrary to popular belief, they are a genetically diverse population, due to the custom of abducting women from neighboring tribes. Many of these tribes are agriculturalists. From Mann et al: "The genetic argument is worthless". This will be important to keep in mind as we interpret the data.

At approximately 14 years old, Masai men are inducted into the warrior class, and are called Muran. For the next 15-20 years, tradition dictates that they eat a diet composed exclusively of cow's milk, meat and blood. Milk is the primary food. Masai cows are not like wimpy American cows, however. Their milk contains almost twice the fat of American cows, more protein, more cholesterol and less lactose. Thus, Muran eat an estimated 3,000 calories per day, 2/3 of which comes from fat. Here is the reference for all this. Milk fat is about 50% saturated. That means the Muran gets 33% of his calories from saturated fat. This population eats more saturated fat than any other I'm aware of.

How's their cholesterol? Remarkably low. Their total serum cholesterol is about half the average American's. I haven't found any studies that broke it down further than total cholesterol. Their blood pressure is also low, and hypertension is rare. Overweight is practically nonexistent. Their electrocardiogram readings show no signs of heart disease. They have exceptionally good endurance, but their grip strength is significantly weaker than Americans of African descent. Two groups undertook autopsies of male Masai to look for artery disease.

The first study, published in 1970, examined 10 males, 7 of which were over 40 years old. They found very little evidence of atherosclerosis, even in individuals over 60. The second study, which is often used as evidence against a high-fat diet, was much more thorough and far more interesting. Mann et al. autopsied 50 Masai men, aged 10 to 65. The single most represented age group was 50-59 years old, at 13 individuals. They found no evidence of myocardial infarction (heart attack) in any of the 50 hearts. What they did find, however, was coronary artery disease. Here's a figure showing the prevalence of "aortic fibrosis", a type of atherosclerotic lesion:


It looks almost binary, doesn't it? What could be causing the dramatic jump in atherosclerosis at age 40? Here's another figure, of total cholesterol (top) and "sudanophilia" (fatty streaks in the arteries, bottom). Note that the Muran period is superimposed (top).


There's clearly a pattern here. Either the Masai men are eating nothing but milk, meat and blood and they're nearly free from atherosclerosis, or they're eating however they please and they have as much atherosclerosis as the average American. There doesn't seem to be much in between.

Here's a quote from the paper that sums it up well:

We believe... that the Muran escapes some noxious dietary agent for a time. Obviously, this is neither animal fat nor cholesterol. The old and the young Masai do have access to such processed staples as flour, sugar, confections and shortenings through the Indian dukas scattered about Masailand. These foods could carry the hypothetical agent."

I know this blog is starting to sound like a broken record, but I'll say it again: you can eat a wide variety of foods and be healthy, except industrial grain products (particularly wheat), sugar, industrial vegetable oil and other processed food. The Masai are just one more example of a group that's healthy when eating a traditional diet.

Scientist Discovers that Only Pills can Control Hypertension

I went to a presentation today by a prominent hypertension researcher. His talk began with a slide that had two pictures side-by-side: one of the late fitness advocate Jim Fixx, and the other of Winston Churchill. Fixx was a marathon runner, while Churchill was inactive, overweight and had a famous appetite. Fixx died of a sudden heart attack at 52, while Churchill lived to 90. The presenter went on to state that this is an example of how genes control CVD risk, implying that despite Fixx's exemplary lifestyle, his genes had condemned him to an early death.

I wanted to jump up and yell "I think you're leaving out the alternate hypothesis: running marathons and stuffing yourself with grains isn't healthy!" But instead I suffered quietly through what ended up being an inane yet informative presentation.

His lab looks for gene variations that affect blood pressure (BP). There's a huge amount of money and research going into this. His lab and others have come up with two classes of mutations:

• Common allele variants that have an insignificant but measurable effect on blood pressure.
• Rare genetic mutations that have a significant effect on BP. The most common affects 1 in 2,000 people in the US.

Despite truckloads of funding and research, they have yet to uncover any gene or combination of genes that accounts for even a fraction of hypertension in Americans. So what's the next step? Keep looking for genes.

I suspect they will never find anything interesting. The reason? Hypertension is tightly linked to lifestyle. It's a quintessential aspect of the "disease of civilization". It's highly responsive to carbohydrate restriction, as a number of clinical trials have shown. Remember the Kuna? They don't get hypertension when they live a non-industrial, grain-free lifestyle (despite eating more salt than the average American), but as soon as they move to the city their hearts explode. It's been demonstrated in a number of other similar cases as well. Genetics are clearly not responsible.

Don't get me wrong, I do think genetics can modify a person's response to a poor lifestyle. But when the lifestyle is healthy, the vast majority of these differences fade away. I have a more thorough discussion of this point here.

If you give just the right dose of poison to a group of animals, 50% will die and 50% will survive (called the EC50 dose). You might then conclude that genetics had determined who lived and died. You wouldn't be wrong, but you'd be missing the point that what killed them was the poison.

The thing that really bothers me about this thinking is it's disempowering. The presenter suggested that the reason for the difference between Fixx and Churchill was their genes. If genes have us in such a tight grip, why bother trying to live well? The only logical solution is to pop hypertension pills and eat cake all day.

My guess is that if they had lived a more natural lifestyle, Fixx would have made it to 90 and Churchill would have been fit and lean.

Genetics and Disease

There is a lot of confusion surrounding the role of genetics in health. It seems like every day the media have a new story about gene X or Y 'causing' obesity, diabetes or heart disease. There are some diseases that are strongly and clearly linked to a gene, such as the disease I study: spinocerebellar ataxia type 7. I do not believe that genetics are the cause of more than a slim minority of health problems however. Part of this is a semantic issue. How do you define the word 'cause'? It's a difficult question, but I'll give you an example of my reasoning and then we'll come back to it.

A classic and thoroughly studied example of genetic factors in disease can be found in the Pima indians of Arizona. Currently, this population eats a version of the American diet, high in refined and processed foods. It also has the highest prevalence of type II diabetes of any population on earth (much higher than the US average), and a very high rate of obesity. One viewpoint is that these people are genetically susceptible to obesity and diabetes, and thus their genes are the cause of their health problems.

However, if you walk across the national border to Mexico, you'll find another group of Pima indians. This population is genetically very similar to the Arizona Pima except they have low rates of obesity and diabetes. They eat a healthier, whole-foods, agriculture-based diet. Furthermore, 200 years ago, the Arizona Pima were healthy as well. So what's the cause of disease here? Strictly speaking, it's both genetics and lifestyle. Both of these factors are necessary for the health problems of the Arizona Pima. However, I think it's more helpful to think of lifestyle as the cause of disease, since that's the factor that changed.

The Pima are a useful analogy for the world in general. They are an extreme example of what has happened to many if not all modern societies. Thus, when we talk about the 'obesity gene' or the 'heart disease gene', it's misleading. It's only the 'obesity gene' in the context of a lifestyle to which we are not genetically adapted.

I do not believe that over half of paleolithic humans were overweight, or that 20% had serious blood glucose imbalances. In fact, studies of remaining populations living naturally and traditionally have shown that they are typically much healthier than industrialized humans. Yet here we are in the US, carrying the very same genes as our ancestors, sick as dogs. That's not all though: we're actually getting sicker. Obesity, diabetes, allergies and many other problems are on the rise, despite the fact that our genes haven't changed.

I conclude that genetics are only rarely the cause of disease, and that the vast majority of health problems in the US are lifestyle-related. Studies into the genetic factors that predispose us to common health problems are interesting, but they're a distraction from the real problems and the real solutions that are staring us in the face. These solutions are to promote a healthy diet, exercise, and effective stress management.