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

+ Author Affiliations

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

+ Author Notes

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

↵†Corresponding author. E-mail: joseph.majzoub@childrens.harvard.edu (J.A.M.); isf20@cam.ac.uk (I.S.F.)

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.

Received for publication 20 November 2012.
Accepted for publication 13 June 2013.

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