A New Understanding of an Old "Obesity Gene"

As you know if you've been following this blog for a while, obesity risk has a strong genetic component.  Genome-wide association studies (GWAS) attempt to identify the specific locations of genetic differences (single-nucleotide polymorphisms or SNPs) that are associated with a particular trait.  In the case of obesity, GWAS studies have had limited success in identifying obesity-associated genes.  However, one cluster of SNPs consistently show up at the top of the list in these studies: those that are near the gene FTO.

As with many of the genes in our genome, different people carry different versions of FTO.  People with two copies of the "fat" version of the FTO SNPs average about 7 pounds (3 kg) heavier than people with two copies of the "thin" version, and they also tend to eat more calories (1, 2).  

Despite being the most consistent hit in these genetic studies, FTO has remained a mystery.  As with most obesity-associated genes, it's expressed in the brain and it seems to respond somewhat to nutritional status.  Yet its function is difficult to reconcile with a role in weight regulation: 

• It's an enzyme that removes methyl groups from RNA, which doesn't immediately suggest a weight-specific function.
• It's not primarily expressed in the brain or in body fat, but in all tissues.
• Most importantly, as far as we know, the different versions of the gene do not result in different tissue levels of FTO, or different activity of the FTO enzyme, so it's hard to understand how they would impact anything at all.  

An important thing to keep in mind is that GWAS studies don't usually pinpoint specific genes.  Typically, they tell us that obesity risk is associated with variability in a particular region of the genome.  If the region corresponds to the location of a single gene, it's a pretty good guess that the gene is the culprit.  However, that's not always the case...

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The Genetics of Obesity, Part III

Genetics Loads the Gun, Environment Pulls the Trigger

Thanks to a WHS reader* for reminding me of the above quote by Dr. Francis Collins, director of the US National Institutes of Health**.  This is a concept that helps reconcile the following two seemingly contradictory observations:

1. Roughly 70 percent of obesity risk is genetically inherited, leaving only 30 percent of risk to environmental factors such as diet and lifestyle.
2. Diet and lifestyle have a large impact on obesity risk.  The prevalence of obesity has tripled in the last 30 years, and the prevalence of extreme obesity has increased by almost 10-fold.  This is presumably not enough time for genetic changes to account for it.

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The Genetics of Obesity, Part II

Rodents Lead the Way

The study of obesity genetics dates back more than half a century.  In 1949, researchers at the Jackson Laboratories identified a remarkably fat mouse, which they determined carried a spontaneous mutation in an unidentified gene.  They named this the "obese" (ob/ob) mouse.  Over the next few decades, researchers identified several other genetically obese mice with spontaneous mutations, including diabetic (db/db) mice, "agouti" (Avy) mice, and "Zucker" (fa/fa) rats.

At the time of discovery, no one knew where the mutations resided in the genome.  All they knew is that the mutations were in single genes, and they resulted in extreme obesity.  Researchers recognized this as a huge opportunity to learn something important about the regulation of body fatness in an unbiased way.  Unbiased because these mutations could be identified with no prior knowledge about their function, therefore the investigators' pre-existing beliefs about the mechanisms of body fat regulation could have no impact on what they learned.  Many different research groups tried to pin down the underlying source of dysfunction: some thought it was elevated insulin and changes in adipose tissue metabolism, others thought it was elevated cortisol, and a variety of other hypotheses.

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The Genetics of Obesity, Part I

Choosing the Right Parents: the Best Way to Stay Lean?

In 1990, Dr. Claude Bouchard and colleagues published a simple but fascinating study demonstrating the importance of genetics in body fatness (1).  They took advantage of one of the most useful tools in human genetics: identical twins.  This is what happens when a single fertilized egg generates two embryos in utero and two genetically identical humans are born from the same womb.   By comparing identical twins to other people who are not genetically identical (e.g., non-identical twins), we can quantify the impact of genes vs. environment on individual characteristics (2).

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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 appears to be 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 I found interesting:

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."

This may suggest that you can eat a wide variety of foods and be healthy, except industrial grain products (particularly white flour), 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.

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.