Editors' ChoiceMetabolism

Accessory to Obesity?

Sci. Signal.  23 Jul 2013:
Vol. 6, Issue 285, pp. ec171
DOI: 10.1126/scisignal.2004524

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. 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. studied two paralogs of the MRAP2 accessory protein, one of which enhanced MC4R responsiveness to α–melanocyte-stimulating hormone, which regulates feeding and growth.

M. Asai, S. Ramachandrappa, M. Joachim, Y. Shen, R. Zhang, N. Nuthalapati, V. Ramanathan, D. E. Strochlic, P. Ferket, K. Linhart, C. Ho, T. V. Novoselova, S. Garg, M. Ridderstråle, C. Marcus, J. N. Hirschhorn, J. M. Keogh, S. O’Rahilly, L. F. Chan, A. J. Clark, I. S. Farooqi, J. A. Majzoub, Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity. Science 341, 275–278 (2013). [Abstract] [Full Text]

J. A. Sebag, C. Zhang, P. M. Hinkle, A. M. Bradshaw, R. D. Cone, Developmental control of the melanocortin-4 receptor by MRAP2 proteins in zebrafish. Science 341, 278–281 (2013). [Abstract] [Full Text]