A research team claims that it has discovered the functional obesity gene. Named IRX3, it interacts with the FTO gene that previously has been viewed as the strongest genetic determinant of obesity risk in humans, according to the scientists, who published their study (“Obesity-associated variants within FTO form long-range functional connections with IRX3”) in Nature.
“Our data strongly suggest that IRX3 controls body mass and regulates body composition,” said senior study author Marcelo Nobrega, Ph.D., 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 of 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, continued Dr. Nobrega.
Hoping to explain these observations, he and his group mapped the behavior of promoters 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.
“A direct link between IRX3 expression and regulation of body mass and composition is demonstrated by a reduction in body weight of 25 to 30% in Irx3-deficient mice, primarily through the loss of fat mass and increase in basal metabolic rate with browning of white adipose tissue,” wrote the investigators. “Finally, hypothalamic expression of a dominant-negative form of Irx3 reproduces the metabolic phenotypes of Irx3-deficient mice. Our data suggest that IRX3 is a functional long-range target of obesity-associated variants within FTO and represents a novel determinant of body mass and composition.”
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.
“What we’ve found is that the switches that control IRX3 are far away from the gene and actually inside the FTO gene,” added Dr. Nobrega. “IRX3 is probably a master regulator of genetic programs in the cells where it is expressed. We’re interested in what its targets are and what they alter. The goal is to identify downstream targets of IRX3 that become models for drug targeting.”
Research on obesity is receiving increasing attention by scientists around the globe. In January,another team reported that five fat genes were responsible for widen girths in humans.