MC4R and Genetic obesity: 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).