Cited by 901Regulation of Appetite and ObesityHypothalamic control of reproductive hormonesEating Disorders and Behaviors

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Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity

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Vaisse, Christian, Clement, Karine, Durand, Emmanuelle, Hercberg, Serge, Guy-Grand, Bernard, Froguel, Philippe·2000·Journal of Clinical Investigation

DOI 10.1172/jci9238PMC PMC314306

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Abstract

By integrating an agonist satiety signal, provided by alpha-melanocyte-stimulating hormone (alpha-MSH), and an antagonist signal, provided by agouti-related protein (AGRP), the melanocortin-4 receptor (MC4-R) is a key element in the hypothalamic control of food intake. Inactivation of the gene encoding this G protein-coupled receptor causes obesity in mice. In humans, frameshift mutations in MC4-R cause an early-onset dominant form of obesity in two families. In this study we find a high frequency (4%) of rare heterozygous MC4-R mutations in a large population of morbidly obese patients. No such mutations were found in controls. By analyzing the phenotypes of the probands carrying these mutations, we demonstrate that these patients display a common, nonsyndromic form of obesity. Interestingly, functional analysis of the mutant receptors indicates that obesity-associated defects in MC4-R range from loss of function to constitutive activation. Transmission of these mutations in the families of the carriers indicates a variable expressivity that is not related to the functional severity of the mutations. This variable expressivity of MC4-R-associated obesity is not due to variations in genes for alpha-MSH or AGRP. Taken together, these results demonstrate that MC4-R mutations are a frequent but heterogeneous genetic cause of morbid obesity.

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Authors: Vaisse, C., Clement, K., Durand, E., Hercberg, S., Guy-Grand, B., & Froguel, P.
Affiliations: Centre National de la Recherche Scientifique (FR)
Hôtel-Dieu de Paris (FR)
University of California, San Francisco (US)
Corresponding author: Vaisse, Christian
ORCID: Vaisse, Christian
Durand, Emmanuelle
Froguel, Philippe
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2000-07-15
Volume: 106
Issue: 2
Pages: 253-262
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci9238
PMC: PMC314306
OpenAlex: W2118192748
Cited by: 897
References: 40
Citations by year: 2026: 11 · 2025: 17 · 2024: 21 · 2023: 26 · 2022: 18 · 2021: 32 · 2020: 27 · 2019: 28 · 2018: 27 · 2017: 22 · 2016: 26 · 2015: 34 · 2014: 36 · 2013: 22 · 2012: 28
FWCI: 20.59
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Danone
Instituto Danone
Servier
Topics: Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Social Sciences › Psychology › Clinical Psychology › Eating Disorders and Behaviors
Keywords: melanocortin-4 receptor, MC4R mutations, morbid obesity, agouti-related protein, alpha-melanocyte-stimulating hormone, G protein-coupled receptors, loss of function, constitutive receptor activation, variable expressivity, genetic heterogeneity
MeSH terms: Adolescent, Adult, Aged, Aged, 80 and over, alpha-MSH, Child, Eating, Female, Genetic Testing, Heterozygote, Humans, Male, Middle Aged, Mutation, Obesity, Morbid, Pedigree, Proteins, Cohort Studies, Frameshift Mutation, Receptors, Corticotropin, Penetrance, Mutation, Missense, Intercellular Signaling Peptides and Proteins, Receptor, Melanocortin, Type 4, Agouti-Related Protein

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Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity

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