Variations in gene expression may underlie increased food intake in obesity

Large-scale genetic studies have identified a number of variations in genes that increase an individual's susceptibility to obesity.

An allelic variant in the intronic region of a gene called fat mass and obesity-associated (FTO) is strongly linked to increased food intake and body weight in humans, but it is unclear how the variant causes these effects.

In this month's issue of the JCI, a research team led by Rudolph Leibel at Columbia University examined how the obesity-risk allele alters the regulation of nearby genes to promote obesity.

Liebel's group found that the allele was associated with reduced expression of FTO and a nearby gene called RPGRIP1L, which encodes a component of the primary cillium. In mice, altered expression of Rpgrip1l was linked to increased food intake and weight gain.

Further, the researchers found that reduced expression of Rpgrip1l in neurons produced deficits in the brain's response to leptin, a hormone that signals satiety, which may produce the observed increases in food intake.

Collectively, this study suggests that the obesity-risk allele mediates its effect in part through changes in expression to neighboring genes and provides new insights into the mechanisms underlying genetic predisposition to obesity in humans.