The role of insulin receptor substrate 2 in hypothalamic and β cell function

Choudhury, A.I. et al. (2005) The role of insulin receptor substrate 2 in hypothalamic and β cell function. Journal of Clinical Investigation, 115(4), pp. 940-950. (doi: 10.1172/JCI24445)

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Insulin receptor substrate 2 (Irs2) plays complex roles in energy homeostasis. We generated mice lacking Irs2 in β cells and a population of hypothalamic neurons (RIPCreIrs2KO), in all neurons (NesCreIrs2KO), and in proopiomelanocortin neurons (POMCCreIrs2KO) to determine the role of Irs2 in the CNS and β cell. RIPCreIrs2KO mice displayed impaired glucose tolerance and reduced β cell mass. Overt diabetes did not ensue, because β cells escaping Cre-mediated recombination progressively populated islets. RIPCreIrs2KO and NesCreIrs2KO mice displayed hyperphagia, obesity, and increased body length, which suggests altered melanocortin action. POMCCreIrs2KO mice did not display this phenotype. RIPCreIrs2KO and NesCreIrs2KO mice retained leptin sensitivity, which suggests that CNS Irs2 pathways are not required for leptin action. NesCreIrs2KO and POMCCreIrs2KO mice did not display reduced β cell mass, but NesCreIrs2KO mice displayed mild abnormalities of glucose homeostasis. RIPCre neurons did not express POMC or neuropeptide Y. Insulin and a melanocortin agonist depolarized RIPCre neurons, whereas leptin was ineffective. Insulin hyperpolarized and leptin depolarized POMC neurons. Our findings demonstrate a critical role for IRS2 in β cell and hypothalamic function and provide insights into the role of RIPCre neurons, a distinct hypothalamic neuronal population, in growth and energy homeostasis.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Selman, Professor Colin
Authors: Choudhury, A.I., Heffron, H., Smith, M.A., Al-Qassab, H., Xu, A.W., Selman, C., Simmgen, M., Clements, M., Claret, M., MacColl, G., Bedford, D.C., Hisadome, K., Diakonov, I., Moosajee, V., Bell, J.D., Speakman, J.R., Batterham, R.L., Barsh, G.S., Ashford, M.L.J., and Withers, D.J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
Journal Name:Journal of Clinical Investigation
Publisher:Americal Society for Clinical Investigation
ISSN (Online):1558-8238
Published Online:01 March 2005
Copyright Holders:Copyright © 2005 American Society for Clinical Investigation
First Published:First published in Journal of Clinical Investigation 115(4):940-950
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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