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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Endogenous Melanocortin System Activity Contributes to the Elevated Arterial Pressure in Spontaneously Hypertensive Rats
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Regulation of thermogenesis by the central melanocortin system
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The Human MC4R Promoter
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Hyperphagia, not hypometabolism, causes early onset obesity in melanocortin-4 receptor knockout mice
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Forebrain melanocortin signaling enhances the hindbrain satiety response to CCK-8
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Intraventricular administration of MSH induces hyperalgesia in rats
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SIM1 Overexpression Partially Rescues Agouti Yellow and Diet-Induced Obesity by Normalizing Food Intake
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Activation of the Melanocortin-4 Receptor Mobilizes Intracellular Free Calcium in Immortalized Hypothalamic Neurons
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Homozygous Null Mutation of the Melanocortin-4 Receptor and Severe Early-Onset Obesity
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Ac-nle-c[asp-his-dphe-arg-trp-lys]-nh2 induces penile erection via brain and spinal melanocortin receptors
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Peripheral Administration of a Melanocortin 4-Receptor Inverse Agonist Prevents Loss of Lean Body Mass in Tumor-Bearing Mice
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Peripheral Administration of the Melanocortin-4 Receptor Antagonist NBI-12i Ameliorates Uremia-Associated Cachexia in Mice
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A Mutation in the Second Transmembrane Region of the CB1 Receptor Selectively Disrupts G Protein Signaling and Prevents Receptor Internalization
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Mechanisms of Cell-surface Rerouting of an Endoplasmic Reticulum-retained Mutant of the Vasopressin V1b/V3 Receptor by a Pharmacological Chaperone
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Prevalence and functionality of paucimorphic and privateMC4Rmutations in a large, unselected European British population, scanned by meltMADGE
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A possible involvement of melanocortin 3 receptor in the regulation of adrenal gland function in the chicken
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Constitutive Activation of G Protein-Coupled Receptors as a Result of Selective Substitution of a Conserved Leucine Residue in Transmembrane Helix III
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α-Melanocyte stimulating hormone prevents fasting-induced suppression of corticotropin-releasing hormone gene expression in the rat hypothalamic paraventricular nucleus
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Lower Metabolic Rate in Individuals Heterozygous for Either a Frameshift or a Functional Missense MC4R Variant
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Adeno-associated virus-mediated knockdown of melanocortin-4 receptor in the paraventricular nucleus of the hypothalamus promotes high-fat diet-induced hyperphagia and obesity
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Molecular Determinants of Human Melanocortin-4 Receptor Responsible for Antagonist SHU9119 Selective Activity
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Differential effects of melanocortin peptides on ingestive behaviour in rats: evidence against the involvement of MC3 receptor in the regulation of food intake
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A novel nonsense mutation in the melanocortin-4 receptor associated with obesity in a Spanish population
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Food deprivation increases the expression of melanocortin-4 receptor in the liver of barfin flounder, Verasper moseri
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Ala67Thr polymorphism in the Agouti‐related peptide gene is associated with inherited leanness in humans
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Syndecan‐3 Modulates Food Intake by Interacting with the Melanocortin/AgRP Pathway
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Association of the MC4R V103I Polymorphism With the Metabolic Syndrome: The KORA Study
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Reduction in corpora lutea number in obese melanocortin-4-receptor-deficient mice
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Corticotropin-releasing hormone mediates α-melanocyte-stimulating hormone-induced anorexigenic action in goldfish
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Constitutive Traffic of Melanocortin-4 Receptor in Neuro2A Cells and Immortalized Hypothalamic Neurons
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Central Melanocortin Receptors Mediate Changes in Food Intake in the Rhesus Macaque
Koegler, F. H., Grove, K. L., Schiffmacher, A. T., Smith, M. S., & Cameron, J. L. (2001) · Endocrinology · doi:10.1210/endo.142.6.8198 · Cited by 57
Molecular and Behavioral Interactions Between Central Melanocortins and Cocaine
Alvaro, J. D., Taylor, J. R., & Duman, R. S. (2003) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.102.040311 · Cited by 57
Melanocortins and opiate addiction
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Participation of α-melanocyte stimulating hormone in ethanol-induced anxiolysis and withdrawal anxiety in rats
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Modulation of melanocortin signaling ameliorates uremic cachexia
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Corticotropin Peptides and Melanotropins Elevate the Level of Adenosine 3′: 5′‐Cyclic Monophosphate in Cultured Murine Brain Cells
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An effect of a missense mutation in the porcine melanocortin‐4 receptor (MC4R) gene on production traits in Polish pig breeds is doubtful
Stachowiak, M., Szydłowski, M., Obarzanek-Fojt, M., & Switonski, M. (2005) · Animal Genetics · doi:10.1111/j.1365-2052.2005.01373.x · Cited by 56
Melanocortin 4 Receptor Gene Variation Is Associated With Severe Obesity in Pima Indians
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Six Novel Mutations in the Proopiomelanocortin and Melanocortin Receptor 4 Genes in Severely Obese Adults Living in Southern Italy
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Unabated anorexic and enhanced thermogenic responses to melanotan II in diet-induced obese rats despite reduced melanocortin 3 and 4 receptor expression
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Cachexia: lessons from melanocortin antagonism
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Effects of Melanocortin Receptor Activation and Blockade on Ethanol Intake: A Possible Role for the Melanocortin-4 Receptor
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Melanocortin Receptors as Targets in the Treatment of Obesity
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Voluntary exercise delays monogenetic obesity and overcomes reproductive dysfunction of the melanocortin-4 receptor knockout mouse
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Hypothalamic pro-opiomelanocortin gene delivery ameliorates obesity and glucose intolerance in aged rats
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Rescuing the Traffic-Deficient Mutants of Rat μ-Opioid Receptors with Hydrophobic Ligands
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Deletions of the N‐terminal regions of the human melanocortin receptors
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Orally Available Selective Melanocortin-4 Receptor Antagonists Stimulate Food Intake and Reduce Cancer-Induced Cachexia in Mice
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MTII-induced reduction of voluntary ethanol drinking is blocked by pretreatment with AgRP-(83–132)
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Central administration of selective melanocortin 4 receptor antagonist HS014 prevents morphine tolerance and withdrawal hyperalgesia
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Melanocortins stimulate proliferation and induce morphological changes in cultured rat astrocytes by distinct transducing mechanisms
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Impact of obesity on renal structure and function in the presence and absence of hypertension: evidence from melanocortin-4 receptor-deficient mice
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Retinoids Assist the Cellular Folding of the Autosomal Dominant Retinitis Pigmentosa Opsin Mutant P23H
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Genetic predisposition to obesity in bulimia nervosa: a mutation screen of the melanocortin-4 receptor gene
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Behavioral processes underlying the intake suppressive effects of melanocortin 3/4 receptor activation in the rat
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Central α-melanocyte-stimulating hormone acts at melanocortin-4 receptor to activate sympathetic nervous system in conscious rabbits
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Melanocortin receptors mediate α-MSH-induced stimulation of neurite outgrowth in neuro 2A cells
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Functional Selectivity of Melanocortin 4 Receptor Peptide and Nonpeptide Agonists: Evidence for Ligand-Specific Conformational States
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Effects of melanocortin receptor ligands on ethanol intake and opioid peptide levels in alcohol-preferring AA rats
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The melanocortin receptor agonist MTII augments the rewarding effect of amphetamine in ad-libitum-fed and food-restricted rats
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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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