Abstract
Melanocortin receptor accessory proteins (MRAPs) are regulators of the melanocortin receptor family. MRAP is an essential accessory factor for the functional expression of the MC2R/ACTH receptor. The importance of MRAP in adrenal gland physiology is demonstrated by the clinical condition familial glucocorticoid deficiency type 2. The role of its paralog melanocortin-2-receptor accessory protein 2 (MRAP2), which is predominantly expressed in the hypothalamus including the paraventricular nucleus, has recently been linked to mammalian obesity. Whole body deletion and targeted brain specific deletion of the Mrap2 gene result in severe obesity in mice. Interestingly, Mrap2 complete knockout (KO) mice have increased body weight without detectable changes to food intake or energy expenditure. Rare heterozygous variants of MRAP2 have been found in humans with severe, early-onset obesity. In vitro data have shown that Mrap2 interaction with the melanocortin-4-receptor (Mc4r) affects receptor signaling. However, the mechanism by which Mrap2 regulates body weight in vivo is not fully understood and differences between the phenotypes of Mrap2 and Mc4r KO mice may point toward Mc4r independent mechanisms.
Highlights
The role of its paralog melanocortin-2-receptor accessory protein 2 (MRAP2), which is predominantly expressed in the hypothalamus including the paraventricular nucleus, has recently been linked to mammalian obesity
The melanocortin agonist ligands for Melanocortin receptors (MCRs), adrenocorticotropic hormone (ACTH) and the melanocyte stimulating hormones αMSH, βMSH, and γMSH, are neuropeptides derived by enzymatic cleavage from proopiomelanocortin (Pritchard et al, 2002)
One study assessed MC2R, MRAP, and MRAP2 expression in human adrenal tissue derived from normal and hyperplastic adrenal gland, and from adrenocortical adenomas and carcinomas (Hofland et al, 2012). Their data suggested that the effect of ACTH stimulation on the expression of the ACTH receptor complex comprising MC2R, MRAP and MRAP2 assists in the production of a functioning complex, the level of MRAP2 being insufficient to reduce its sensitivity to ACTH
Summary
Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK Edited by: Olivier Kah, Centre National de la Recherche Scientifique UMR 6026, France Specialty section: This article was submitted to Neuroendocrine Science, a section of the journal
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