Abstract
Melanocortin receptor accessory protein 2 (MRAP2) is a transmembrane accessory protein predominantly expressed in the brain. Both global and brain-specific deletion of Mrap2 in mice results in severe obesity. Loss-of-function MRAP2 mutations have also been associated with obesity in humans. Although MRAP2 has been shown to interact with MC4R, a G protein-coupled receptor with an established role in energy homeostasis, appetite regulation and lipid metabolism, the mechanisms through which loss of MRAP2 causes obesity remains uncertain. In this study, we used two independently derived lines of Mrap2 deficient mice (Mrap2tm1a/tm1a) to further study the role of Mrap2 in the regulation of energy balance and peripheral lipid metabolism. Mrap2tm1a/tm1a mice have a significant increase in body weight, with increased fat and lean mass, but without detectable changes in food intake or energy expenditure. Transcriptomic analysis showed significantly decreased expression of Sim1, Trh, Oxt and Crh within the hypothalamic paraventricular nucleus of Mrap2tm1a/tm1a mice. Circulating levels of both high-density lipoprotein and low-density lipoprotein were significantly increased in Mrap2 deficient mice. Taken together, these data corroborate the role of MRAP2 in metabolic regulation and indicate that, at least in part, this may be due to defective central melanocortin signalling.
Highlights
Melanocortin receptor accessory protein (MRAP) and its paralogue Melanocortin receptor accessory protein 2 (MRAP2) are a recently identified class of small, single-pass transmembrane domain accessory proteins (Chan et al 2009, Novoselova et al 2013)
Melanocortin receptor accessory protein (MRAP) and its paralogue MRAP2 are a recently identified class of small, single-pass transmembrane domain accessory proteins (Chan et al 2009, Novoselova et al 2013). Both MRAP and MRAP2 have been shown to interact with the melanocortin receptors (MCRs), a family of G protein-coupled receptors (GPCRs) with diverse physiological function stimulated by pro-opiomelanocortin (POMC) derived peptide agonists such as adrenocorticotropin hormone (ACTH) and α-MSH (Cone 2005, Chan et al 2009)
MRAP2 is predominantly expressed in the central nervous system and hypothalamus, in particular within the paraventricular nucleus (PVN), a region known to have a role in energy homeostasis (Chan et al 2009)
Summary
Melanocortin receptor accessory protein (MRAP) and its paralogue MRAP2 are a recently identified class of small, single-pass transmembrane domain accessory proteins (Chan et al 2009, Novoselova et al 2013). Both MRAP and MRAP2 have been shown to interact with the melanocortin receptors (MCRs), a family of G protein-coupled receptors (GPCRs) with diverse physiological function stimulated by pro-opiomelanocortin (POMC) derived peptide agonists such as adrenocorticotropin hormone (ACTH) and α-MSH (Cone 2005, Chan et al 2009). Further evidence for a link with MC4R signalling came from a study on the role of Mrap in zebrafish feeding and growth (Sebag et al 2013)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
