Researchers have discovered that the obesity-associated elements within the gene FTO interact with IRX3, a distant gene on the genome that appears to be the functional obesity gene.
Senior study author Marcelo Nobrega, PhD, associate professor of human genetics at the University of Chicago, said that their data strongly suggest that IRX3 controls body mass and regulates body composition, asserting that any association between FTO and obesity appears due to the influence of IRX3.
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.
Co-author Jose Luis Gomez-Skarmeta, PhD, a geneticist at the Andalusian Center of Developmental Biology in Sevilla, Spain, said that instead they 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. 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.
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 study has been published online in journal Nature.