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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