Over the past 20 years, insights from human and mouse genetics have illuminated the central role of the brain leptin-melanocortin pathway in the control of mammalian food intake, with genetic disruption resulting in extreme obesity, and more subtle polymorphic variation influencing the population distribution of body-weight. At the end of 2020, the Food & Drug Administration (FDA) approved setmelanotide, a melanocortin 4 receptor agonist, for use in individuals with severe obesity due to either pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) deficiency.

Here, we will chart the history of the melanocortin pathway, explore its pharmacology, genetics and physiology, and tell the story of how a neuropeptidergic circuit managed to find its way to becoming an important druggable obesity target.

Unravelling the genetics of the subset of severe obesity has revealed the importance of the melanocortin pathway in appetitive control; coupling this with studying the molecular pharmacology of compounds that bind the melanocortin receptors has brought a new drug to the market for obesity. This process provides a template of drug discovery for complex disorders, which in the case of setmelanotide took 25 years to go from a single gene to an approved drug.