Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 341 (6143): 275-278

Copyright © 2013 by the American Association for the Advancement of Science

Loss of Function of the Melanocortin 2 Receptor Accessory Protein 2 Is Associated with Mammalian Obesity

Masato Asai,1,2 Shwetha Ramachandrappa,3 Maria Joachim,1 Yuan Shen,1 Rong Zhang,1 Nikhil Nuthalapati,1 Visali Ramanathan,1 David E. Strochlic,1 Peter Ferket,4 Kirsten Linhart,1,* Caroline Ho,1 Tatiana V. Novoselova,5 Sumedha Garg,3 Martin Ridderstråle,6 Claude Marcus,7 Joel N. Hirschhorn,1,8 Julia M. Keogh,3 Stephen O’Rahilly,3 Li F. Chan,5 Adrian J. Clark,5 I. Sadaf Farooqi,3,{dagger} Joseph A. Majzoub1,{dagger}

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.

1 Division of Endocrinology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
2 Departments of Pathology, Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
3 University of Cambridge Metabolic Research Laboratories and National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK.
4 Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA.
5 William Harvey Research Institute, Centre for Endocrinology Queen Mary, University of London Barts and The London School of Medicine and Dentistry, London EC1M 6BQ, UK.
6 Department of Clinical Sciences, Lund University, Malmö, Sweden, and Steno Diabetes Center, DK-2820 Gentofte, Denmark.
7 Department for Clinical Science, Intervention and Technology, Karolinska Institute, Division of Pediatrics, National Childhood Obesity Centre, S-141 86 Stockholm, Sweden.
8 Department of Genetics, Harvard Medical School and Broad Institute, Cambridge, MA 02142, USA.

* Present address: Department of Internal Medicine, KH Salem, University of Heidelberg, 69120 Heidelberg, Germany.

{dagger} Corresponding author. E-mail: joseph.majzoub{at} (J.A.M.); isf20{at} (I.S.F.)

Obesity, genetic risk, and environment.
A. I. F. Blakemore and J. L. Buxton (2014)
BMJ 348, g1900
   Full Text »    PDF »
Structural determinants regulating cell surface targeting of melanocortin receptors.
A. R. Rodrigues, D. Sousa, H. Almeida, and A. M. Gouveia (2013)
J. Mol. Endocrinol. 51, R23-R32
   Abstract »    Full Text »    PDF »
Developmental Control of the Melanocortin-4 Receptor by MRAP2 Proteins in Zebrafish.
J. A. Sebag, C. Zhang, P. M. Hinkle, A. M. Bradshaw, and R. D. Cone (2013)
Science 341, 278-281
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882