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

Asai, Masato, Ramachandrappa, Shwetha, Joachim, Maria, Shen, Yuan, Zhang, Rong, Nuthalapati, Nikhil, Ramanathan, Visali, Strochlic, David E., Ferket, Peter, Linhart, Kirsten, Ho, Caroline, Novoselova, Tatiana ORCID: https://orcid.org/0000-0002-2394-4667, Garg, Sumedha, Ridderstråle, Martin, Marcus, Claude, Hirschhorn, Joel N., Keogh, Julia M., O’Rahilly, Stephen, Chan, Li F., Clark, Adrian, Farooqi, Sadaf and Majzoub, Joseph A. (2013) Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity. Science, 341 (6143) . pp. 275-278. ISSN 0036-8075 [Article] (doi:10.1126/science.1233000)

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 AMP, 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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