Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity
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Accessory to Obesity?: Melanocortin receptors are a family of cell membrane receptors that control diverse physiological functions. Mutations in the gene encoding melanocortin 4 receptor (MC4R) are a cause of familial early-onset obesity. Asai et al. (p. 275 ) studied the function of an accessory protein for MC4R signaling, MRAP2, and found that mice genetically deficient in MRAP2 develop severe obesity. Sequencing of MRAP2 in unrelated, severely obese humans revealed one individual with a clearly disruptive genetic variant, suggesting that MRAP2 mutations might also be a rare cause of human obesity. In a zebrafish model, Sebag et al. (p. 278 ) studied two paralogs of the MRAP2 accessory protein, one of which enhanced MC4R responsiveness to α–melanocyte-stimulating hormone, which regulates feeding and growth.
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In experimental models of obesity, metabolic defects involving substrate partitioning and energy expenditure may manifest without (or before) increased food intake.
“In experimental models of obesity, metabolic defects involving substrate partitioning and energy expenditure may manifest without (or before) increased food intake, demonstrating the conceptual plausibility of this fundamental feature of the CIM (60, 112–114).”
From The carbohydrate-insulin model: A physiological perspective on the obesity pandemic (2021) · cites this paper as [112]
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References 20 · Cited by 290
- Authors
- Asai, M., Ramachandrappa, S., Joachim, M., Shen, Y., Zhang, R., Nuthalapati, N., Ramanathan, V., Strochlic, D. E., Ferket, P., Linhart, K., Ho, C., Novoselova, T. V., Garg, S., Ridderstråle, M., Marcus, C., Hirschhorn, J. N., Keogh, J. M., O’Rahilly, S., Chan, L. F., Clark, A. J., Farooqi, I. S., & Majzoub, J. A.
- Affiliations
- Boston Children's Hospital (US)
- University of Cambridge (GB)
- North Carolina State University (US)
- Queen Mary University of London (GB)
- Lund University (SE)
- Karolinska Institutet (SE)
- Broad Institute (US)
- Corresponding author
- Linhart, Kirsten
- Farooqi, I. Sadaf
- Majzoub, Joseph A.
- ORCID
- Venue
- Science
- Published
- 2013-07-19
- Volume
- 341
- Issue
- 6143
- Pages
- 275-278
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3788688
- OpenAlex
- W2031545914
- Cited by
- 290
- References
- 20
- Citations by year
- 2026: 17 · 2025: 17 · 2024: 18 · 2023: 18 · 2022: 29 · 2021: 32 · 2020: 31 · 2019: 20 · 2018: 22 · 2017: 22 · 2016: 17 · 2015: 17 · 2014: 20 · 2013: 9 · 2012: 1
- FWCI
- 11.23
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Middlesex University Research Repository (Middlesex University Of London) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Wellcome Trust (098497)
- Novo Nordisk Fonden (NNF11OC1014660)
- Japan Society for the Promotion of Science (25460493)
- National Institute of Mental Health (T32MH020017)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK075787, T32DK007699)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD018655)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- MRAP2, melanocortin-4 receptor, obesity, cyclic AMP, rare variants, body weight regulation, melanocortin receptors
- MeSH terms
- Adolescent, Animals, Body Weight, Carrier Proteins, Child, Child, Preschool, Energy Metabolism, Female, Humans, Male, Obesity, Body Mass Index, Gene Deletion, Mice, Knockout, Receptor, Melanocortin, Type 4, Adaptor Proteins, Signal Transducing, Mice, Young Adult, Receptor Activity-Modifying Proteins
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