Attractin-Like Protein 1 (ATRNL1): 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. The MC4R agonist Imcivree has been approved for the treatment of certain genetic obesity syndromes. Here we demonstrate that the membrane-spanning protein Attractin-like protein 1 (ATRNL1) directly interacts with MC4R to amplify its signaling in cells and that expression of ATRNL1 potentiates the activation of MC4R neurons by MC4R agonists in mice. Disruption of ATRNL1 in the PVN of the hypothalamus causes increased food intake and obesity, which cannot be rescued by MC4R agonist treatment. In exomes from 927 children with severe early-onset obesity, we identified 21 rare ATRNL1 variants. Eleven of 17 variants studied in cells impaired ATRNL1-mediated regulation of MC4R signaling, including variants ultra-rare or absent from UK Biobank and other populations. Cumulatively, these findings establish ATRNL1 as an important regulator of mammalian energy homeostasis.