Setmelanotide, a second-generation small-molecule MC4R agonist currently in clinical trials, causes significant weight loss in complete POMC deficiency (Kühnen et al., 2016) and other genetic obesity syndromes characterized by a loss of melanocortin tone (Clément et al., 2018, 2020; Collet et al., 2017; Haws et al., 2020). This evidence concerns the gene MC4R and hyperinsulinemic hypoglycemia, familial, 4.