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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}childrens.harvard.edu (J.A.M.); isf20{at}cam.ac.uk (I.S.F.)


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