The recent approval of Setmelanotide, an MC4R agonist, for treating obesity caused by deficiencies in proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or Leptin Receptor (Markham, 2021), has heightened scientific interest in the effects of MCRs on feeding and energy balance (Table 1). Here, MC4R is linked to obesity due to melanocortin 4 receptor deficiency.