Setmelanotide, a selective MC4R agonist, has recently been approved by the FDA for the treatment of rare forms of monogenic obesity characterized by LEPR or proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency, a pivotal enzyme to process POMC into α-MSH that stimulates MC4R (and MC3R) to reduce food intake (9). The gene discussed is LEPR; the disease is obesity due to melanocortin 4 receptor deficiency.