When weight loss is the goal, the equation seems simple enough: consume fewer calories and burn more of them exercising. But for some people, losing and keeping off the weight is much more difficult for reasons that can include a genetic component. While there are rare genetic causes of extreme obesity, the strongest common genetic contributor discovered so far is a variant found in an intron of the FTO gene. Variations in this untranscribed region of the gene have been tied to differences in body mass and a risk of obesity . For the one in six people of European descent born with two copies of the risk variant, the consequence is carrying around an average of an extra 7 pounds .
Now, NIH-funded researchers reporting in The New England Journal of Medicine  have figured out how this gene influences body weight. The answer is not, as many had suspected, in regions of the brain that control appetite, but in the progenitor cells that produce white and beige fat. The researchers found that the risk variant is part of a larger genetic circuit that determines whether our bodies burn or store fat. This discovery may yield new approaches to intervene in obesity with treatments designed to change the way fat cells handle calories.
The team—led by Melina Claussnitzer of Beth Israel Deaconess Medical Center, Boston, and Manolis Kellis of the Massachusetts Institute of Technology (MIT), Cambridge—started with a basic question: where in the body does this variant act to influence weight? For the answer, the team turned to the NIH-funded Roadmap Epigenomics Project.
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