Review

. 2021 Jun:48:101206.

doi: 10.1016/j.molmet.2021.101206. Epub 2021 Mar 6.

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

Affiliations

¹ MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. Electronic address: gshy2@cam.ac.uk.
² Université de Paris, BFA, UMR 8251, CNRS, Paris, France. Electronic address: klctnn@gmail.com.
³ MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. Electronic address: ams299@medschl.cam.ac.uk.
⁴ Department of Medicinal Chemistry and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA 55455. Electronic address: koerp005@umn.edu.
⁵ Department of Medicinal Chemistry and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA 55455. Electronic address: erics063@umn.edu.
⁶ Metabolism, Diabetes, and Obesity Programme, Monash Biomedicine Discovery Institute, and Department of Physiology, Monash University, Clayton, Victoria, Australia. Electronic address: Stephanie.Simonds@monash.edu.
⁷ Department of Medicinal Chemistry and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA 55455. Electronic address: lars5005@umn.edu.
⁸ Université de Paris, BFA, UMR 8251, CNRS, Paris, France. Electronic address: serge.luquet@u-paris.fr.
⁹ Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: iain.clarke@unimelb.edu.au.
¹⁰ Rhythm Pharmaceuticals, Boston, MA, USA 02116. Electronic address: ssharma@rhythmtx.com.
¹¹ Assistance Publique Hôpitaux de Paris, Nutrition Department, Pitié-Salpêtrière Hospital, Paris, France, Sorbonne Université, INSERM, Nutrition and Obesity: Systemic Approaches (NutriOmics) Research Unit, Paris, France. Electronic address: karine.clement@aphp.fr.
¹² Metabolism, Diabetes, and Obesity Programme, Monash Biomedicine Discovery Institute, and Department of Physiology, Monash University, Clayton, Victoria, Australia. Electronic address: michael.cowley@monash.edu.
¹³ Department of Medicinal Chemistry and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA 55455. Electronic address: chaskell@umn.edu.
¹⁴ Rhythm Pharmaceuticals, Boston, MA, USA 02116. Electronic address: lex@riffitnow.com.
¹⁵ Department of Translational Neuroscience, UMCU Brain Centre, University Medical Centre Utrecht, Utrecht University, the Netherlands; Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Sweden. Electronic address: R.A.H.Adan@umcutrecht.nl.

PMID: 33684608
PMCID: PMC8050006
DOI: 10.1016/j.molmet.2021.101206

Review

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

Giles S H Yeo et al. Mol Metab. 2021 Jun.

. 2021 Jun:48:101206.

doi: 10.1016/j.molmet.2021.101206. Epub 2021 Mar 6.

Authors

Affiliations

¹ MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. Electronic address: gshy2@cam.ac.uk.
² Université de Paris, BFA, UMR 8251, CNRS, Paris, France. Electronic address: klctnn@gmail.com.
³ MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. Electronic address: ams299@medschl.cam.ac.uk.
⁴ Department of Medicinal Chemistry and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA 55455. Electronic address: koerp005@umn.edu.
⁵ Department of Medicinal Chemistry and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA 55455. Electronic address: erics063@umn.edu.
⁶ Metabolism, Diabetes, and Obesity Programme, Monash Biomedicine Discovery Institute, and Department of Physiology, Monash University, Clayton, Victoria, Australia. Electronic address: Stephanie.Simonds@monash.edu.
⁷ Department of Medicinal Chemistry and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA 55455. Electronic address: lars5005@umn.edu.
⁸ Université de Paris, BFA, UMR 8251, CNRS, Paris, France. Electronic address: serge.luquet@u-paris.fr.
⁹ Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: iain.clarke@unimelb.edu.au.
¹⁰ Rhythm Pharmaceuticals, Boston, MA, USA 02116. Electronic address: ssharma@rhythmtx.com.
¹¹ Assistance Publique Hôpitaux de Paris, Nutrition Department, Pitié-Salpêtrière Hospital, Paris, France, Sorbonne Université, INSERM, Nutrition and Obesity: Systemic Approaches (NutriOmics) Research Unit, Paris, France. Electronic address: karine.clement@aphp.fr.
¹² Metabolism, Diabetes, and Obesity Programme, Monash Biomedicine Discovery Institute, and Department of Physiology, Monash University, Clayton, Victoria, Australia. Electronic address: michael.cowley@monash.edu.
¹³ Department of Medicinal Chemistry and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA 55455. Electronic address: chaskell@umn.edu.
¹⁴ Rhythm Pharmaceuticals, Boston, MA, USA 02116. Electronic address: lex@riffitnow.com.
¹⁵ Department of Translational Neuroscience, UMCU Brain Centre, University Medical Centre Utrecht, Utrecht University, the Netherlands; Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Sweden. Electronic address: R.A.H.Adan@umcutrecht.nl.

PMID: 33684608
PMCID: PMC8050006
DOI: 10.1016/j.molmet.2021.101206

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.

Keywords: Genetics; Hypothalamus; Melanocortin; Obesity; Pharmacology; Therapy.

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Figures

**Figure 1**
Schematic illustrating POMC (red) and AgRP (blue) neuronal projections from the arcuate nucleus of the hypothalamus (ARH) to the lateral hypothalamus (LH), paraventricular nucleus of the hypothalamus (PVH), central nucleus of the amygdala (CEA), bed nucleus of the stria terminalis (BST), lateral parabrachial nucleus (LPB), reticular formation (RET), dorsal motor nucleus of the vagus (DMV), area postrema (AP), and nucleus of the solitary tract (NTS). POMC and AgRP neurons arise in the ARH adjacent to the median eminence (ME) and project widely. POMC neurons in the NTS have a more restricted set of projections. Both sets of neurons appear able to receive neural and endocrine signals from the body.

**Figure 2**
Structures of the synthetic and endogenous human melanocortin ligands. The commonly hypothesised active sequences are highlighted in blue (endogenous agonists and synthetic ligands) and red (endogenous antagonists).

See this image and copyright information in PMC

References

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

Affiliations

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

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Miscellaneous