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Discovery of Body Weight Regulation by the Protein MRAP2

Researchers discovered that the MRAP2 protein regulates growth and body weight in animals, and MRAP2 deficiency may contribute to severe obesity in humans. Two research teams studied MRAP2 because its suspected biological partner, a protein called MC4R, is known to be critical in metabolism; people born with genetic deficiencies in MC4R develop severe obesity as children. To investigate MRAP2 further, one team generated mice with a genetic mutation that caused a deficiency of this protein. Without MRAP2, the mice became extremely obese, even when their food was limited so they could eat only as much as normal mice. The MRAP2-deficient mice only attained a normal weight when the researchers further restricted their allotted food to less than what a typical mouse would eat—a finding that may help explain why weight control through dieting is a constant challenge for people with genetic predisposition to obesity.

Because MRAP2-deficient mice fed normal portions still became obese, the researchers realized that MRAP2 may affect body weight in ways other than through appetite and food intake. They thus examined whether MRAP2 influences how much the mice move, their calorie burning, or body temperature, but found no differences between mice with and without MRAP2. Although these results alone do not clarify the mechanism by which MRAP2 functions, additional studies by both teams, using mice and another experimental organism, zebrafish, revealed several clues. MRAP2, like MC4R, works in the brain; MRAP2 and MC4R physically interact; and MRAP2 influences MC4R’s activity. Finally, one of the research teams analyzed genomic data from people whose obesity began in childhood, and found that a few of these individuals had rare genetic variants that may impair MRAP2. The variants were not seen in non‑obese people.

This research sheds light on a potential rare genetic form of obesity and yields insights that may lead to the design of new therapeutics that target MRAP2.