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...

Read more �

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.

Read more �

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.

Read more �

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).

Read more �