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Targeting the central melanocortin system for the treatment of metabolic disorders

Nature Reviews Endocrinology volume 19, pages 507–519 (2023)Cite this article

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Abstract

A large body of preclinical and clinical data shows that the central melanocortin system is a promising therapeutic target for treating various metabolic disorders such as obesity and cachexia, as well as anorexia nervosa. Setmelanotide, which functions by engaging the central melanocortin circuitry, was approved by the FDA in 2020 for use in certain forms of syndromic obesity. Furthermore, the FDA approvals in 2019 of two peptide drugs targeting melanocortin receptors for the treatment of generalized hypoactive sexual desire disorder (bremelanotide) and erythropoietic protoporphyria-associated phototoxicity (afamelanotide) demonstrate the safety of this class of peptides. These approvals have also renewed excitement in the development of therapeutics targeting the melanocortin system. Here, we review the anatomy and function of the melanocortin system, discuss progress and challenges in developing melanocortin receptor-based therapeutics, and outline potential metabolic and behavioural disorders that could be addressed using pharmacological agents targeting these receptors.

Key points

  • Several monogenic and polygenic obesity syndromes involve defective leptin–melanocortin signalling.

  • The non-specific melanocortin peptide agonist setmelanotide, which acts via the MC4R to inhibit food intake and produce weight loss, has been approved by the FDA for the treatment of proopiomelanocortin deficiency, leptin receptor deficiency and Bardet–Biedl syndrome.

  • Two non-specific melanocortin agonist peptides, bremelanotide and afamelanotide, have been approved for the treatment of hypoactive sexual desire disorder and erythropoietic protoporphyria-associated phototoxicity, respectively, demonstrating the safety of this new drug class.

  • Melanocortin therapeutics might also have applications in eating disorders, such as cachexia and anorexia nervosa, and disorders of neuroendocrine function.

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Fig. 1: Microcircuitry of the central melanocortin system.
Fig. 2: Macro-circuitry of the central melanocortin system in mice.
Fig. 3: MC3R controls energy rheostasis.
Fig. 4: MC4R signalling pathways.
Fig. 5: Monogenic obesity syndromes involving the melanocortin system.

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Acknowledgements

The authors acknowledge the support of NIH grants DK126715 (R.D.C.), F32HD095620 (P.S.), K99DK127065 (P.S.), R00 DK127065 (P.S.), Brain and Behaviour Research Foundation Young Investigator Award (P.S.), Foundation for Prader Willi Research (P.S.), Courage Therapeutics (R.D.C.) and The Klarman Family Foundation (R.D.C.). The authors thank R. Arora (Life Sciences Institute, University of Michigan) for assistance in preparing the first drafts of the figures.

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  1. School of Molecular and Cellular Biology, College of Liberal Arts and Sciences, University of Illinois Urbana-Champaign, Champaign, IL, USA

    Patrick Sweeney

  2. Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA

    Luis E. Gimenez, Ciria C. Hernandez & Roger D. Cone

  3. Department of Molecular and Integrative Physiology, School of Medicine, University of Michigan, Ann Arbor, MI, USA

    Roger D. Cone

  4. Department of Molecular, Cellular, and Developmental Biology, College of Literature Science and the Arts, University of Michigan, Ann Arbor, MI, USA

    Roger D. Cone

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Sweeney, P., Gimenez, L.E., Hernandez, C.C. et al. Targeting the central melanocortin system for the treatment of metabolic disorders. Nat Rev Endocrinol 19, 507–519 (2023). https://doi.org/10.1038/s41574-023-00855-y

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