Gene thought to cause obesity works indirectly

Researchers have discovered a “genetic switch” that determines whether people will burn extra calories or save them as fat.

A genetic variant tightly linked to obesity causes fat-producing cells to become energy-storing white fat cells instead of energy-burning beige fat, researchers report online August 19 in the New England Journal of Medicine.

Previously scientists thought that the variant, in a gene known as FTO (originally called fatso), worked in the brain to increase appetite. The new work shows that the FTO gene itself has nothing to do with obesity, says coauthor Manolis Kellis, a computational biologist at MIT and the Broad Institute. But the work may point to a new way to control body fat.

In humans and many other organisms, genes are interrupted by stretches of DNA known as introns. Kellis and Melina Claussnitzer of Harvard Medical School and colleagues discovered that a genetic variant linked to increased risk of obesity affects one of the introns in the FTO gene. It does not change the protein produced from the FTO gene or change the gene’s activity. Instead, the variant doubles the activity of two genes, IRX3 and IRX5, which are involved in determining which kind of fat cells will be produced.

FTO’s intron is an enhancer, a stretch of DNA needed to control activity of far-away genes, the researchers discovered. Normally, a protein called ARID5B squats on the enhancer and prevents it from dialing up activity of the fat-determining genes. In fat cells of people who have the obesity-risk variant, ARID5B can’t do its job and the IRX genes crank up production of energy-storing white fat.

When researchers turned down activity of the IRX genes in human fat cells, the cells became energy-burning beige fat cells. Researchers also disrupted the IRX3 gene in fat cells of normal-weight mice. Those mice lost more than 50 percent of their body fat, even though they ate and exercised as much as other mice did. The mice were also protected from gaining weight on a high-fat diet. Disrupting the IRX3 gene in a part of the brain called the hypothalamus, which helps control appetite, did not have the same effect. That result indicates that the white-to-beige fat switch works in fat tissue, not in the brain.

About 40 percent of Europeans and 42 percent of Southeast Asians carry the obesity-risk variant, Kellis says. Only 5 percent of Africans do. But “every human on the planet has that genetic circuit,” so researchers may be able to manipulate the IRX genes to eliminate obesity, he says. “This is perhaps the secret to curing obesity and we’re going to throw everything at it.”

But benefits could be a long way off, Clifford Rosen of the Maine Medical Research Institute in Scarborough and Julie Ingelfinger of Massachusetts General Hospital write in an editorial accompanying the paper. “As yet, there is still no simple path to an anti-obesity drug that can be derived from this research,” they write. But researchers might use similar strategies to those in this study to figure out how genetic variants are linked to other diseases. Many of those variants don’t fall within genes.