MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency

Genetic defects underlying the melanocortin-4 receptor(MC4R) signaling pathway lead to severe obesity. Three severely obeseLEPR-deficient individuals were administered the MC4R agonist setmelanotide, resulting in substantial and durable reductions in hyperphagia and body weight over an observation period of 45–61 weeks. Compared to formerly developed and tested MC4R agonists, setmelanotidehas the unique capability of activating nuclear factor of activated T cell ( NFAT) signaling and restoring function of this signaling pathway for selected MC4R variants. Our data demonstrate the potency of setmelanotidein treatment of individuals with diverse MC4R-related pathway deficiencies.