Genetic defects underlying the melanocortin-4 receptor (MC4R) signaling pathway lead to severe obesity. Three severely obese LEPR-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, setmelanotide has 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 setmelanotide in treatment of individuals with diverse MC4R-related pathway deficiencies.

MHO is a stable status in childhood obesity as long as pubertal status remains stable. Due to the strong association between puberty and MUO status, the concept of MHO is questionable, at least in pubertal children.

Our study demonstrated an encouraging effect of lifestyle intervention in extremely obese children ≤10 years at the end of intervention and 1 year later, but only a limited effect in extremely obese adolescents >10 years.