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  • Review Article
  • Published:

Multifaceted actions of melanin-concentrating hormone on mammalian energy homeostasis

Nature Reviews Endocrinology volume 17, pages 745–755 (2021)Cite this article

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Abstract

Melanin-concentrating hormone (MCH) is a small cyclic peptide expressed in all mammals, mainly in the hypothalamus. MCH acts as a robust integrator of several physiological functions and has crucial roles in the regulation of sleep–wake rhythms, feeding behaviour and metabolism. MCH signalling has a very broad endocrine context and is involved in physiological functions and emotional states associated with metabolism, such as reproduction, anxiety, depression, sleep and circadian rhythms. MCH mediates its functions through two receptors (MCHR1 and MCHR2), of which only MCHR1 is common to all mammals. Owing to the wide variety of MCH downstream signalling pathways, MCHR1 agonists and antagonists have great potential as tools for the directed management of energy balance disorders and associated metabolic complications, and translational strategies using these compounds hold promise for the development of novel treatments for obesity. This Review provides an overview of the numerous roles of MCH in energy and glucose homeostasis, as well as in regulation of the mesolimbic dopaminergic circuits that encode the hedonic component of food intake.

Key points

  • Melanin-concentrating hormone (MCH) is a highly conserved, 19 amino acid peptide, and MCH-immunoreactive neuronal cell bodies exist in a wide range of species (fish, reptiles, birds and mammals).

  • MCH is found mainly in the lateral hypothalamic area and zona incerta, and it exerts its effects through MCH receptor 1 (MCHR1) and MCHR2 in mammals (except rodents and lagomorphs).

  • In addition to stimulating food intake via homeostatic and hedonic pathways, MCH reduces energy expenditure and locomotor activity, and induces adiposity, weight gain, glucose intolerance and peripheral lipid storage.

  • MCH is not a meal-initiation hormone; instead, MCH signalling amplifies food intake after feeding initiation, thereby increasing sucrose and glucose intake.

  • MCH neurons are active during sleep and mostly silent during wakefulness; however, MCH neurons can also be active during wakefulness.

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Fig. 1: Metabolic actions elicited by MCH.
Fig. 2: The role of MCH in homeostatic control of feeding.
Fig. 3: The role of MCH in intracerebroventricular volume transmission.
Fig. 4: The role of MCH in hedonic control of feeding.
Fig. 5: Mechanisms and pathways that mediate the peripheral actions of MCH.

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Acknowledgements

The authors’ research work is supported by grants from Fondos Europeos de Desarrollo Regional (FEDER) and Ministerio de Ciencia, Innovación y Universidades–Agencia Estatal de Investigación (to C.D., BFU2017-87721; R.N., RTI2018-099413-B-I00; M.L., RTI2018-101840-B-I00); Xunta de Galicia (to R.N., 2016-PG057 and ED431C 2020/12) and grants ED431G 2019/02, Fundación BBVA to R.N., Fundación Atresmedia (to R.N.), European Foundation for the Study of Diabetes (to R.N.) and Fundación la Caixa (to R.N., HR18-00100 and M.L., LCF/PR/HR19/52160022). The research leading to these results has also received funding from the European Community’s H2020 Framework Programme under ERC Synergy Grant-2019-WATCH-810331 to M. Schwaninger, V.P. and R.N. CIBERobn and CIBERehd are initiatives of the Instituto de Salud Carlos III (ISCIII) of Spain, which is supported by FEDER funds. M. Schneeberger also acknowledges support from the National Institute of Diabetes and Digestive Kidney Diseases (NIDDK) grant K99 DK120869. O.A.-M. is funded by research contract ‘Miguel Servet’ (CP20/00146) from ISCIII, co-financed by the European Social Fund.

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Authors and Affiliations

  1. Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Spain

    Omar Al-Massadi

  2. CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain

    Omar Al-Massadi, Carlos Dieguez, Miguel López & Ruben Nogueiras

  3. Department of Physiology, CIMUS, University of Santiago de Compostela–Instituto de Investigación Sanitaria, Santiago de Compostela, Spain

    Carlos Dieguez, Miguel López & Ruben Nogueiras

  4. Laboratory of Molecular Genetics, Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA

    Marc Schneeberger

  5. Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany

    Markus Schwaninger

  6. Univ. Lille, Inserm, CHU Lille, Lille Neuroscience and Cognition, Laboratory of Development and Plasticity of the Neuroendocrine Brain, UMR-S1172, EGID, Lille, France

    Vincent Prevot

  7. Galician Agency of Innovation (GAIN), Xunta de Galicia, Santiago de Compostela, Spain

    Ruben Nogueiras

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Contributions

O.A.-M. and R.N. wrote the manuscript. All authors reviewed and/or edited the manuscript before submission. Additionally, C.D., M. Schneeberger., M.L. and M. Schwaninger made substantial contributions to discussions of the article content.

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Nature Reviews Endocrinology thanks C. Cavadas, who co-reviewed with S. Carmo-Silva; J.-L. Nahon; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Reverse pharmacology

Also known as target-based drug discovery, this technique involves screening libraries of small molecules to identify compounds that bind with high affinity to the target molecule, which can then be investigated for therapeutic efficacy.

In silico data mining

Interrogation of large-scale genomic and proteomic data sets using known gene or amino acid sequences to identify novel related genes and proteins having at least partial homology or identity with the sequence of interest.

Unimolecular polypharmacy

Macromolecular agents developed to act on multiple targets; examples include peptides engineered to have dual receptor–agonist behaviour.

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Al-Massadi, O., Dieguez, C., Schneeberger, M. et al. Multifaceted actions of melanin-concentrating hormone on mammalian energy homeostasis. Nat Rev Endocrinol 17, 745–755 (2021). https://doi.org/10.1038/s41574-021-00559-1

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