The melanocortin pathway and energy homeostasis: From discovery to obesity therapy

Abstract

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.

Obesity: Epidemiology, Pathophysiology, and Therapeutics

“…The FDA also approved the MC4R agonist-Setmelanotide for use in individuals with The gel pieces increase the volume and elasticity of the stomach and small intestine contents, contributing to a feeling of fullness and inducing weight loss. Setmelanotide (Imcivree) (85) Adults and children ages 6 and older An agonist of the MC4R, used in individuals with severe obesity due to either POMC, PCSK1, or LEPR deficiency, and should not be used for other types of obesity such as general obesity. Other medications that curb your desire to eat include •Phentermine (Adipex, Superenza)…”

“…severe obesity due to either POMC, PCSK1 (proprotein convertase subtilisin/kexin type 1), or LEPR (leptin receptor) deficiency at the end of 2020 (85).…”

“…The U.S. FDA (Food and Drug Administration) approved some new pharmacotherapy drugs for short-term obesity treatment ( Table 1 ) and since Lorcaserin was withdrawn, there are only four [Naltrexone-Bupropion (Contrave), Orlistat (Xenical, Alli), Liraglutide (Saxenda) and Phentermine-Topiramate (Qsymia)] approved in addition to Gelesis which is now the fifth, have been approved for long-term use ( 84 , 86 , 87 ). The FDA also approved the MC4R agonist-Setmelanotide for use in individuals with severe obesity due to either POMC, PCSK1 (proprotein convertase subtilisin/kexin type 1), or LEPR (leptin receptor) deficiency at the end of 2020 ( 85 ).…”

Obesity, POMC, and POMC-processing Enzymes: Surprising Results From Animal Models

“…Peptide products derived from POMC exert their actions primarily though the actions of 2 different classes of receptors, melanocortin receptors (MCRs) and endorphin/opioid receptors ( 6 ). There are 5 melanocortin receptors, each with distinct functions and tissue distributions ( 16-19 ). Except for MC2R, which is expressed mainly in the adrenal medulla and binds selectively to ACTH, all the other MCRs bind all MSH peptides (α, β, and γ) as well as ACTH, albeit with slight differences in affinity ( 6 , 16 ).…”

“…There are 5 melanocortin receptors, each with distinct functions and tissue distributions ( 16-19 ). Except for MC2R, which is expressed mainly in the adrenal medulla and binds selectively to ACTH, all the other MCRs bind all MSH peptides (α, β, and γ) as well as ACTH, albeit with slight differences in affinity ( 6 , 16 ). Of the MCRs, only MC3R and MC4R are highly expressed in the brain, and MC4R is especially abundant in hypothalamic areas associated with feeding/body weight regulation.…”