Cited by 531Regulation of Appetite and ObesityHypothalamic control of reproductive hormonesNeuropeptides and Animal Physiology

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The Melanocortin-4 Receptor: Physiology, Pharmacology, and Pathophysiology

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Tao, Ya-Xiong·2010·Endocrine Reviews

DOI 10.1210/er.2009-0037PMC PMC3365848

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Abstract

The melanocortin-4 receptor (MC4R) was cloned in 1993 by degenerate PCR; however, its function was unknown. Subsequent studies suggest that the MC4R might be involved in regulating energy homeostasis. This hypothesis was confirmed in 1997 by a series of seminal studies in mice. In 1998, human genetic studies demonstrated that mutations in the MC4R gene can cause monogenic obesity. We now know that mutations in the MC4R are the most common monogenic form of obesity, with more than 150 distinct mutations reported thus far. This review will summarize the studies on the MC4R, from its cloning and tissue distribution to its physiological roles in regulating energy homeostasis, cachexia, cardiovascular function, glucose and lipid homeostasis, reproduction and sexual function, drug abuse, pain perception, brain inflammation, and anxiety. I will then review the studies on the pharmacology of the receptor, including ligand binding and receptor activation, signaling pathways, as well as its regulation. Finally, the pathophysiology of the MC4R in obesity pathogenesis will be reviewed. Functional studies of the mutant MC4Rs and the therapeutic implications, including small molecules in correcting binding and signaling defect, and their potential as pharmacological chaperones in rescuing intracellularly retained mutants, will be highlighted.

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Authors: Tao, Y.-X.
Affiliations: Auburn University (US)
Corresponding author: Tao, Ya-Xiong
ORCID: Tao, Ya-Xiong
Venue: Endocrine Reviews
Publisher: The Endocrine Society
Published: 2010-08-01
Volume: 31
Issue: 4
Pages: 506-543
ISSN: 0163-769X (ISSN-L)
1945-7189
DOI: 10.1210/er.2009-0037
PMC: PMC3365848
OpenAlex: W2120361515
Cited by: 531
References: 507
Citations by year: 2026: 25 · 2025: 32 · 2024: 34 · 2023: 34 · 2022: 31 · 2021: 41 · 2020: 41 · 2019: 33 · 2018: 29 · 2017: 32 · 2016: 21 · 2015: 29 · 2014: 39 · 2013: 47 · 2012: 30
FWCI: 16.04
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Endocrine Reviews (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Diabetes and Digestive and Kidney Diseases (R15DK077213)
Topics: Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords: melanocortin-4 receptor, energy homeostasis, monogenic obesity, MC4R mutations, cachexia, cardiovascular function, glucose homeostasis, lipid homeostasis, drug abuse, pain perception, neuroinflammation, anxiety, receptor pharmacology, ligand binding, receptor signaling pathways, pharmacological chaperones, obesity pathogenesis, small molecule drugs
MeSH terms: Amino Acid Sequence, Animals, Cachexia, Cardiovascular System, Cloning, Molecular, Energy Metabolism, Gene Expression Regulation, Glucose, Homeostasis, Humans, Molecular Sequence Data, Mutation, Obesity, Organ Specificity, Reproduction, Sexual Behavior, Signal Transduction, Sequence Alignment, Receptor, Melanocortin, Type 4, Lipid Metabolism

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The Melanocortin-4 Receptor: Physiology, Pharmacology, and Pathophysiology

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