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

Giles S.H. Yeo, Daniela Herrera Moro Chao, Anna Maria Siegert, Zoe M. Koerperich, Mark D. Ericson, Stephanie E. Simonds, Courtney M. Larson, Serge Luquet, Iain Clarke, Shubh Sharma, Karine Clément, Michael A. Cowley, Carrie Haskell-Luevano, Lex Van Der Ploeg, Roger A.H. Adan

Research output: Contribution to journalReview articlepeer-review

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.

Original languageEnglish (US)
Article number101206
JournalMolecular Metabolism
Volume48
Early online dateMar 6 2021
DOIs
StateE-pub ahead of print - Mar 6 2021

Bibliographical note

Publisher Copyright:
© 2021 The Authors

Keywords

  • Genetics
  • Hypothalamus
  • Melanocortin
  • Obesity
  • Pharmacology
  • Therapy

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