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Cited by 42Regulation of Appetite and ObesityHypothalamic control of reproductive hormonesReceptor Mechanisms and Signaling

A human obesity-associated MC4R mutation with defective Gq/11α signaling leads to hyperphagia in mice

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Metzger, Peter J., Zhang, Aileen, Carlson, Bradley A., Sun, Hui, Cui, Zhenzhong, Li, Yongqi, Jahnke, Marshal T., Layton, Daniel R. +6 more·2024·Journal of Clinical Investigation
DOI 10.1172/jci165418PMC PMC10869179
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Abstract

Melanocortin 4 receptor (MC4R) mutations are the most common cause of human monogenic obesity and are associated with hyperphagia and increased linear growth. While MC4R is known to activate Gsα/cAMP signaling, a substantial proportion of obesity-associated MC4R mutations do not affect MC4R/Gsα signaling. To further explore the role of specific MC4R signaling pathways in the regulation of energy balance, we examined the signaling properties of one such mutant, MC4R (F51L), as well as the metabolic consequences of MC4RF51L mutation in mice. The MC4RF51L mutation produced a specific defect in MC4R/Gq/11α signaling and led to obesity, hyperphagia, and increased linear growth in mice. The ability of a melanocortin agonist to acutely inhibit food intake when delivered to the paraventricular nucleus (PVN) was lost in MC4RF51L mice, as well as in WT mice in which a specific Gq/11α inhibitor was delivered to the PVN; this provided evidence that a Gsα-independent signaling pathway, namely Gq/11α, significantly contributes to the actions of MC4R on food intake and linear growth. These results suggest that a biased MC4R agonist that primarily activates Gq/11α may be a potential agent to treat obesity with limited untoward cardiovascular and other side effects.

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  • MC4R signalling involves multiple G-protein-mediated pathways, including Gsα/cAMP and Gαq/PLC signalling.

    “MC4R signalling involves multiple G-protein-mediated pathways, including Gsα/cAMP and Gαq/PLC signalling, and different patterns of signalling bias among different pathways are associated with distinct phenotypes and treatment responses (111, 112).”

    From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [112]

  • Different patterns of signalling bias among MC4R pathways are associated with distinct phenotypes and treatment responses.

    “MC4R signalling involves multiple G-protein-mediated pathways, including Gsα/cAMP and Gαq/PLC signalling, and different patterns of signalling bias among different pathways are associated with distinct phenotypes and treatment responses (111, 112).”

    From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [112]

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Cited by

Sorted by citations

Authors
Metzger, P. J., Zhang, A., Carlson, B. A., Sun, H., Cui, Z., Li, Y., Jahnke, M. T., Layton, D. R., Gupta, M. B., Liu, N., Kostenis, E., Gavrilova, O., Chen, M., & Weinstein, L. S.
Affiliations
  • National Institutes of Health (US)
  • University of Bonn (DE)
Corresponding author
Weinstein, Lee S.
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2024-01-04
Volume
134
Issue
4
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
DOI
10.1172/jci165418
PMC
PMC10869179
OpenAlex
W4390579079
Cited by
42
References
5
Citations by year
2026: 14 · 2025: 20 · 2024: 8
FWCI
8.47
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Clinical Investigation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute for Diabetes, Digestive and Kidney Diseases (Intramural Research Program)
  • Deutsche Forschungsgemeinschaft (290847012/FOR2372)
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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
melanocortin-4 receptor, monogenic obesity, hyperphagia, linear growth, food intake regulation, paraventricular nucleus, melanocortin agonists, biased agonists, obesity treatment
MeSH terms
Animals, Humans, Hyperphagia, Mutation, Obesity, Signal Transduction, Receptor, Melanocortin, Type 4, Mice

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