When the first powerful, common gene behind obesity was reported this spring, scientists were excited but also left scratching their heads. No one, including the diabetes researchers who uncovered it, had any idea how the gene--FTO--worked. Now, a group has taken the first steps toward deciphering why the FTO protein weighs down the scales.
FTO surfaced during a hunt for genes behind type 2 diabetes, but researchers soon recognized that its real role was in obesity (Science, 13 April, p. 185). Although obesity has long been considered partly genetic, genes have been tough to come by. The Science study, which included almost 39,000 people, concluded that having two copies of a certain FTO variant increased weight by about 3 kg--the first clear example of a common obesity gene. Then came the hard part: What does FTO do and how does it do it?
To begin answering that, a team from several British institutions considered FTO from different vantage points. At the University of Cambridge, U.K., geneticist Stephen O'Rahilly and his colleagues tried to understand what the FTO protein might do in an animal. In mice, they found high levels of FTO in the brain's hypothalamus, which helps regulate energy balance in the body. Mice that had been denied food had 60% less FTO in one part of their hypothalamus than did those that had eaten normally, hinting that FTO might play a role in appetite.
At the University of Oxford, U.K., researchers zoomed in closer, looking at the sequence of the FTO protein. This revealed that the protein closely resembles enzymes that repair DNA by removing a chemical unit known as a methyl group. Further work confirmed that the FTO protein could demethylate DNA. There are pieces still missing, admits Oxford enzymologist Christopher Schofield, one of the research leaders: the gene or genes that the FTO enzyme demethylates, and how that might affect obesity. The findings are reported online 8 November in Science.
"It's a really crucial, important first step," says Andrew Hattersley of Peninsula Medical School in Exeter, U.K., part of the team that initially discovered the FTO gene. But it's not yet clear, Hattersley and Schofield agree, how FTO alters body weight and whether it really is working through appetite. A transgenic mouse that lacks FTO might help answer this question--and scientists are eagerly working toward creating one.
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