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The role of insulin receptor substrate 2 in hypothalamic and β cell function
Agharul I. Choudhury, … , Michael L.J. Ashford, Dominic J. Withers
Agharul I. Choudhury, … , Michael L.J. Ashford, Dominic J. Withers
Published April 1, 2005
Citation Information: J Clin Invest. 2005;115(4):940-950. https://doi.org/10.1172/JCI24445.
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Article Metabolism

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

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Abstract

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.

Authors

Agharul I. Choudhury, Helen Heffron, Mark A. Smith, Hind Al-Qassab, Allison W. Xu, Colin Selman, Marcus Simmgen, Melanie Clements, Marc Claret, Gavin MacColl, David C. Bedford, Kazunari Hisadome, Ivan Diakonov, Vazira Moosajee, Jimmy D. Bell, John R. Speakman, Rachel L. Batterham, Gregory S. Barsh, Michael L.J. Ashford, Dominic J. Withers

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Hypothalamic function in RIPCreIrs2KO, NesCreIrs2KO, and POMCCreIrs2KO m...
Hypothalamic function in RIPCreIrs2KO, NesCreIrs2KO, and POMCCreIrs2KO mice. (A) Body weight was measured in 12-week-old male mice of the indicated genotypes. (B) Total body fat was determined by MRI in 16-week-old male mice of the indicated genotypes. (C) Cumulative 24-hour food intake was measured in 12-week-old male mice of the indicated genotypes. (D) Fasting blood leptin levels of 12-week-old male mice of the indicated genotypes were measured after a 16-hour overnight fast. (E–G) Cumulative food intake, percent reduction in food intake compared with baseline, and reduction in bodyweight were measured over a 3-day period of treatment with leptin (5 mg/kg) or vehicle in 6–8-week-old male mice of the indicated genotypes. (H) Food intake and fasting leptin levels were determined in 5-week-old male mice of the indicated genotypes. Data in A–H data represent the mean ± SEM for 8–10 animals of each genotype. *P < 0.05, **P < 0.01, and ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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