Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity

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. ClarkI. Sadaf Farooqi, Joseph A. Majzoub

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121 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)275-278
Number of pages4
JournalScience
Volume341
Issue number6143
DOIs
Publication statusPublished - 2013

All Science Journal Classification (ASJC) codes

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    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., ... Majzoub, J. A. (2013). Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity. Science, 341(6143), 275-278. https://doi.org/10.1126/science.1233000