Scientists Prove What Fat People Have Been Saying All Along

Scientists have found a “genetic switch” that makes the difference between whether your body stores extra calories as fat or burns them off. In a study published last month in the New England Journal of Medicine, researchers say they found that a genetic variation linked to obesity makes fat-producing cells become an energy-storing kind of white fat cells instead of energy-burning type of brown fat. 

browning of white adipose tissue has physiological relevance and that disorders of mitochondrial function and brown fat may play a role in pathophysiological aspects of obesity

Previously scientists thought a generic variation to the FTO gene caused changes in the brain that increased a person’s appetite. The study’s researchers, including coauthor Manolis Kellis of Massachusetts Institute of Technology and the Broad Institute now say the FTO gene actually has nothing to do with obesity.
But their findings may still reveal new methods for controlling body fat.

The generic variation doesn’t change the FTO gene’s activity, instead it increases the activity of two other genes (IRX3 and IRX5), which Kellis, Melina Claussnitzer of Harvard Medical School, and their colleagues say are involved in determining which kind of fat cells will be produced.

In humans and many other organisms, genes are interrupted by stretches of DNA known as introns. Researchers discovered FTO’s intron is what’s known as an enhancer, which controls activity of far-away genes. Usually this intron is paired with a protein, ARID5B, which keeps it from really ratcheting up the activity of these fat-determining genes. But the scientists found that people who have the obesity-risk variant, the ARID5B protein can’t do its job and the IRX genes start to crank out energy-storing white fat.

When the researchers dialed back the IRX genes in human fat cells, the cells transformed from energy-storing fat cells to their energy-burning beige cousins. For the study, the scientists also disrupted the IRX3 gene in the fat cells of normal-weight mice causing the mice to lose more than 50 percent of their body fat, even though they continued to eat and exercise in the same quantities as other mice did.

This suggests that weight differences may not be due to a person eating more or exercising less. Two people could eat and exercise the same and the one with the genetic variation could become obese while the other does not

To verify whether the “fat switch” gene had an impact on appetite, the researchers disrupted the IRX3 gene in the hypothalamus, a part of the brain which helps control appetite. It did not have the same effect as it did in the fat cells. Those result confirmed that the white-to-beige fat switch works in fat tissue, not in the brain.
Kellis says nearly 40 percent of those with European-heritage and 42 percent of those with Southeast Asia roots carry the obesity-risk variant. Although only 5 percent of African decedents have the gene, the researcher believes manipulating the the IRX genes could eliminate obesity across all ethnic backgrounds.

“This is perhaps the secret to curing obesity,” Kellis declared. “And we’re going to throw everything at it.”

But that day could be a long way off, caution Clifford Rosen of the Maine Medical Research Institute and Julie Ingelfinger of Massachusetts General Hospital 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,” Rosen and Ingelfinger write.