Rare loss-of-function mutations of melanocortin-2-receptor accessory protein 2 (MRAP2) have been associated with severe, early-onset obesity in humans. Whole body deletion and targeted brain specific deletion of the Mrap2 gene resulted in severe obesity in mice [1]. In vitro data have shown Mrap2 interaction with the melanocortin-4-receptor (MC4R) affecting receptor signalling as a consequence. However, the mechanism by which Mrap2 regulates body weight in vivo is less well understood with differences between Mrap2 and Mc4r knockout (KO) mice phenotypes. In this study we show that, consistently with the previous work, Mrap2 KO mice have severe early obesity without detectable changes to food intake or energy expenditure. To further investigate the in vivo role of Mrap2 we used a plasma membrane enrichment technique to look at the hypothalamic Mc4r protein surface expression in the mutant mice compared with the wild-type. It was found that Mrap2 KO caused a significant decrease of the levels of Mc4r protein in the plasma membrane fraction suggesting reduced trafficking of the receptor to the cell surface. Thus, our data suggest that in vivo Mrap2 mediates hypothalamic Mc4r surface expression and taken together, this work corroborates the role of Mrap2 in obesity as a regulator of melanocortin pathway.
Obesity – A Physiological Perspective (Newcastle, UK) (2014) Proc Physiol Soc 32, PC050
Poster Communications: Melanocortin 2 receptor accessory protein 2 (Mrap2) is associated with obesity and mediates hypothalamic melanocortin-4-receptor trafficking in vivo
T. Novoselova1, R. Larder2, D. Rimmington2, C. Lelliott3, E. Wynn3, S. O'Rahilly2, A. Clark2, D. Logan3, T. P. Coll2, L. F. Chan1
1. Centre for Endocrinology, Queen Mary University of London, London, London, United Kingdom. 2. University of Cambridge Metabolic Research Laboratories, MRC Metabolic Disease Unit, Wellcome Trust-MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, Cambridge, Cambridge, United Kingdom. 3. Wellcome Trust Sanger Institute, Cambridge, Cambridge, United Kingdom.
View other abstracts by:
Where applicable, experiments conform with Society ethical requirements.