Background Over the past 20 years, insights from human and mouse genetics have illuminated the central role of the brain leptin-melanocortin pathway in controlling mammalian food intake, with genetic disruption resulting in extreme obesity, and more subtle polymorphic variations influencing the population distribution of body weight. At the end of 2020, the U.S. Food and 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. Scope of review Herein, we chart the melanocortin pathway's history, explore its pharmacology, genetics, and physiology, and describe how a neuropeptidergic circuit became an important druggable obesity target. Major conclusions 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 melanocortin receptors has brought a new obesity drug to the market. This process provides a drug discovery template for complex disorders, which for setmelanotide took 25 years to transform from a single gene into an approved drug.

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Obesity is a major risk factor for many common diseases and has a significant heritable component. While clinical and large-scale population studies have identified several genes harbouring rare alleles with large effects on obesity risk, there are likely many unknown genes with highly penetrant effects remaining. To this end, we performed whole exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare, loss of function variants in two genes - BSN and APBA1 - with effects on BMI substantially larger than well-established obesity genes such as MC4R. One in ~6500 individuals carry a heterozygous protein truncating variant (PTV) in BSN, which confers a 6.6, 3.7 and 3-fold higher risk of severe obesity (BMI >40kg/m2), non-alcoholic fatty liver disease and type 2 diabetes, respectively. In contrast to most other obesity-related genes, rare variants in BSN and APBA1 had no apparent effect on childhood adiposity. Furthermore, BSN PTVs magnified the influence of common genetic variants associated with BMI, with a common polygenic score exhibiting an effect on BMI twice as large in BSN PTV carriers than non-carriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human iPSC-derived hypothalamic neurons. These approaches highlighted a network of differentially expressed genes that were collectively enriched for genomic regions associated with BMI, and suggest a role for degenerative neuronal synaptic function and neurotransmitter release in the etiology of obesity.