Researchers think they've hit on why a common obesity gene causes weight gain: Those who carry a version of it don't feel full after eating and take in extra calories. That's because the variant of the FTO gene in question, which one in six individuals carry, leads to higher levels of ghrelin, a hormone involved in mediating appetite and the body's response to food, researchers have discovered. While most studies on FTO have relied on mice, the new work analyzed blood samples and brain scans from humans.
"This is a very exciting piece of research," says geneticist Andrew Hattersley of the Peninsula Medical School in Exeter, U.K., who was not involved in the new study. "There is a lot of work that's been done on the mechanism of FTO in animals, but you have to be careful about applying those lessons to people. So it's nice to finally see work done in humans."
Hattersley was part of a team that in 2007 reported that people who had one version of the FTO gene, called AA, weighed an average of 3 kilograms more than those with the TT version of the gene. Since then, studies in mice have shown that in everyone, there are high levels of the FTO protein in brain areas that control energy balance. Researchers have also found that animals with the AA version tend to eat more and prefer high-fat food compared with those with the TT version. But why FTO had this effect wasn't known.
Rachel Batterham, an endocrine and obesity researcher at University College London, thought that gut hormones that mediate the body's response to eating could be the missing link between FTO and food intake. One such hormone is ghrelin, known to be produced by gut cells to stimulate hunger. So Batterham and her colleagues measured levels of ghrelin in the blood of nonobese men with the AA or TT versions of FTO. In those with the TT variant, ghrelin levels rose before a meal, when the person experienced hunger, and fell after eating, as expected. But in those with the obesity-associated AA version, ghrelin levels stayed relatively high even after eating. Moreover, the AA individuals reported a faster increase in hunger after a test meal. And MRI scans revealed that, when the test subjects were shown images of food before or after eating, brain activity in areas associated with motivation and rewards remained high before and after the meal in AA individuals. This suggests that the increased ghrelin levels were impacting the brain's response to food—which "fits very well with what we already know the effects of ghrelin," Batterham says.
But could higher ghrelin levels be unrelated to FTO? The researchers don't think so, in part because they found that in isolated human cells, increased levels of FTO protein led to more ghrelin production. The reason this happens, the group showed, is because that the FTO protein actually alters the ghrelin gene, causing methyl chemical groups to be removed, a so-called epigenetic modification that impacts how much protein the ghrelin gene produces. The AA gene variant, the researchers report online today in The Journal of Clinical Investigation, removed more methyl groups from the gene, leading to increased levels of the hunger hormone.
Whether that proves true, the full story is FTO remains to be uncovered, Hattersley says. "What we don't know is whether FTO is changing many things that alter appetite, of which ghrelin is just one," he says. "I suspect human appetite and obesity is more complex than a single hormone."
Neurobiologist Tamas Horvath of Yale University agrees. "This is a beautiful piece of work at face value," he says. "But I think it's reasonable to continue pursuing many other avenues to see what else might be going on here."