Attractin-like protein 1 is an essential partner of MC4R to regulate body weight.

The melanocortin 4 receptor (MC4R) plays a critical role in the central control of energy homeostasis, and its disruption causes severe early-onset obesity. MC4R signaling is tightly regulated by endogenous agonists and antagonists, as well as the accessory protein MRAP2. The single transmembrane protein attractin-like protein 1 (ATRNL1) is a known interactor of MC4R, however, its effect on MC4R signaling and physiological function is not well understood. Here we show that ATRNL1 interacts with MC4R to amplify its signaling in cells and that expression of ATRNL1 potentiates agonist-induced activation of MC4R neurons. Deletion of Atrnl1 in MC4R neurons increased food intake and body weight in rodents. In exomes from 1,623 children with severe early-onset obesity, we identified multiple rare ATRNL1 variants that impair ATRNL1-mediated regulation of MC4R signaling. Cumulatively, these findings establish ATRNL1 as an important regulator of mammalian energy homeostasis.