Setmelanotide, a highly selective MC4R agonist with a preferential Gqα/G11α pathway stimulation, is approved for specific causes of monogenic obesity upstream of the MC4R (pro-opiomelanocortin deficiency, proprotein convertase subtilisin/kexin type 1, leptin receptor deficiency) (9). The gene discussed is PCSK1; the disease is obesity due to melanocortin 4 receptor deficiency.