Loss of Mrap2 is associated with Sim 1 deficiency and increased circulating cholesterolReportar como inadecuado


Loss of Mrap2 is associated with Sim 1 deficiency and increased circulating cholesterol


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Publication Date: 2016-04-22

Alternative Title: Mrap2 deficiency in obesity

Journal Title: Journal of Endocrinology

Publisher: Bioscientifica

Language: English

Type: Article

Metadata: Show full item record

Citation: Novoselova, T. V., Larder, R., Rimmington, D., Lelliott, C., Wynn, E. H., Gorrigan, R. J., Tate, P. H., et al. (2016). Loss of Mrap2 is associated with Sim 1 deficiency and increased circulating cholesterol. Journal of Endocrinology

Description: This is the author accepted manuscript. The final version is available from Bioscientifica via http://dx.doi.org/10.1530/JOE-16-0057

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 (Mrap2^(tm1a/tm1a)) to further study the role of Mrap2 in the regulation of energy balance and peripheral lipid metabolism. Mrap2^(tm1a/tm1a) mice have a significant increase in body weight, with increased fat and lean mass, but without detectable changes to food intake or energy expenditure. Transcriptomic analysis showed significantly decreased expression of Sim1, Trh, Oxt and Crh within the hypothalamic paraventricular nucleus (PVN) of Mrap2^(tm1a/tm1a) mice. Circulating levels of both high-density lipoprotein (HDL) and low-density lipoprotein (LDL) 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.

Keywords: obesity, melanocortin, accessory protein, metabolism, MC4R, MRAP2, SIM1, OXT, AVP, CRH, TRH

Sponsorship: We would like to thank our funding bodies: The Medical Research Council UK (MRC/Academy of Medical Sciences Clinician Scientist Fellowship Grant G0802796, to L.F.C, supporting T.V.N), Society for Endocrinology Early Career award to T.V.N, the Wellcome Trust (Grant No. 098051) to D.W.L, C.L, E.H.W and for the MGP generation and phenotyping of the C57BL/6N background mice. R J G is supported by a Wellcome Clinical Research Training Fellowship (grant No. WT092024MA). RL, DR, SOR and APC are funded by the Medical Research Council (MRC) Metabolic Disease Unit (MRC_MC_UU_12012/1). L. G was supported by Biotechnology and Biological Sciences Research Council (BBSRC), award BB/L00267/1 and Rosetrees Trust . The authors wish to thank Sanger Mouse Genetics Project and Research Support Facility staff for generating and providing mouse phenotyping information, Natasha Karp for statistical input on the MGP mouse data, Keith Burling for insulin analysis and David Jackson for help with manuscript preparation.

Identifiers:

This record's URL: http://dx.doi.org/10.1530/JOE-16-0057https://www.repository.cam.ac.uk/handle/1810/255869





Autor: Novoselova, T. V.Larder, R.Rimmington, D.Lelliott, C.Wynn, E. H.Gorrigan, R. J.Tate, P. H.Guasti, L.The Sanger Mouse Genetics Proj

Fuente: https://www.repository.cam.ac.uk/handle/1810/255869



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