‘Master regulator’ of obesity? Distant IRX3 gene appears to interact with obesity-related FTO gene mutations

The study appears online March 12 in Nature.

“Our data strongly suggest that IRX3 controls body mass and regulates body composition,” said senior study author Marcelo Nobrega, PhD, associate professor of human genetics at the University of Chicago. “Any association between FTO and obesity appears due to the influence of IRX3.”

Mutations to introns (noncoding portions) of the gene FTO have been widely investigated after genome-wide association studies revealed a strong link between FTO and obesity and diabetes. Yet overexpressing or deleting FTO in animal models affects whole body mass and composition, not just fat, and experiments have failed to show that these obesity-linked introns affect the function of the FTO gene itself.

Hoping to explain these observations, Nobrega and his team mapped the behavior of promoters — regions of DNA that activate gene expression — located within one million base pairs on either side of the FTO gene. In adult mice brains, where FTO was thought to affect metabolic function, they discovered that the promoter that turns on FTO did not interact with obesity-associated FTO introns.

“Instead, we found that the promoter for IRX3, a gene several hundred thousand base pairs away, did interact with these introns, as well as a large number of other elements across the vast genetic distance we studied,” said co-author Jose Luis Gomez-Skarmeta, PhD, a geneticist at the Andalusian Center of Developmental Biology in Sevilla, Spain. The researchers found a similar pattern of interactions in humans after analyzing data from the ENCODE project, which they confirmed with experiments on human cells.

Using data from 153 brain samples from individuals of European ancestry, they discovered that the mutations to FTO introns that affected body weight are associated with IRX3 expression, but not FTO. Obesity-related FTO introns enhanced the expression of IRX3, functioning as regulatory elements. The FTO gene itself did not appear to play a role in this interaction.

“Regulatory elements are switches that turn genes on and off. What we’ve found is that the switches that control IRX3 are far away from the gene and actually inside the FTO gene,” says Nobrega.

IRX3 deficient mice are thin

To verify the role of IRX3, the researchers engineered mice without the IRX3 gene. These mice were significantly leaner than their normal counterparts. They weighed about 30 percent less, primarily through reduced fat.

The decrease in weight gain occurred despite normal levels of food consumption and physical activity. When fed