Abstract |
Melanocortin receptor accessory proteins (MRAPs) modulate signaling of melanocortin receptors in vitro. To investigate the physiological role of brain-expressed melanocortin 2 receptor accessory protein 2 (MRAP2), we characterized mice with whole-body and brain-specific targeted deletion of Mrap2, both of which develop severe obesity at a young age. Mrap2 interacts directly with melanocortin 4 receptor (Mc4r), a protein previously implicated in mammalian obesity, and it enhances Mc4r-mediated generation of the second messenger cyclic adenosine monophosphate, suggesting that alterations in Mc4r signaling may be one mechanism underlying the association between Mrap2 disruption and obesity. In a study of humans with severe, early-onset obesity, we found four rare, potentially pathogenic genetic variants in MRAP2, suggesting that the gene may also contribute to body weight regulation in humans.
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Authors | Masato Asai, Shwetha Ramachandrappa, Maria Joachim, Yuan Shen, Rong Zhang, Nikhil Nuthalapati, Visali Ramanathan, David E Strochlic, Peter Ferket, Kirsten Linhart, Caroline Ho, Tatiana V Novoselova, Sumedha Garg, Martin Ridderstråle, Claude Marcus, Joel N Hirschhorn, Julia M Keogh, Stephen O'Rahilly, Li F Chan, Adrian J Clark, I Sadaf Farooqi, Joseph A Majzoub |
Journal | Science (New York, N.Y.)
(Science)
Vol. 341
Issue 6143
Pg. 275-8
(Jul 19 2013)
ISSN: 1095-9203 [Electronic] United States |
PMID | 23869016
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Adaptor Proteins, Signal Transducing
- Carrier Proteins
- MC4R protein, mouse
- MRAP2 protein, human
- MRAP2 protein, mouse
- Receptor Activity-Modifying Proteins
- Receptor, Melanocortin, Type 4
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Topics |
- Adaptor Proteins, Signal Transducing
- Adolescent
- Animals
- Body Mass Index
- Body Weight
(genetics)
- Carrier Proteins
(genetics)
- Child
- Child, Preschool
- Energy Metabolism
(genetics)
- Female
- Gene Deletion
- Humans
- Male
- Mice
- Mice, Knockout
- Obesity
(genetics, metabolism)
- Receptor Activity-Modifying Proteins
(genetics, metabolism)
- Receptor, Melanocortin, Type 4
(genetics, metabolism)
- Young Adult
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