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

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Yeo, Giles SH 
Chao, Daniela Herrera Moro 
Siegert, Anna-Maria 
Koerperich, Zoe M 
Ericson, Mark D 


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.



Genetics, Hypothalamus, Melanocortin, Obesity, Pharmacology, Therapy, Animals, Anti-Obesity Agents, Drug Approval, Drug Discovery, Energy Metabolism, History, 20th Century, History, 21st Century, Homeostasis, Humans, Melanocortins, Mice, Obesity, Receptor, Melanocortin, Type 4, Signal Transduction, United States, alpha-MSH

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Mol Metab

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Elsevier BV
MRC (MR/S026193/1)
MRC (MC_UU_00014/1)
Medical Research Council (MC_UU_12012/5)
MRC (MC_UU_00014/5)
Biotechnology and Biological Sciences Research Council (BB/S017593/1)
Medical Research Council (MC_PC_12012)