A family of insulin receptor substrate (IRS) proteins mediates the pleiotropic effects of insulin and insulin-like growth factor 1 (IGF-1) on cellular function by recruiting several intracellular signalling networks. Conventional murine knockout strategies have started to reveal distinct physiological roles for the IRS proteins. Deletion of Irsl produces a mild metabolic phenotype with compensated insulin resistance but also causes marked growth retardation. In contrast, mice lacking IRS-2 display nearly normal growth but develop diabetes owing to a combination of peripheral insulin resistance and β-cell failure. As well as the classical metabolic events regulated by insulin signalling pathways, studies in lower organisms have implicated insulin/IGF-1 signalling pathways in the control of food intake and reproductive function. Our analysis of IRS-2 knockout mice shows that female mice are infertile owing to defects in the hypothalamus, pituitary and gonad. IRS-2−1 mice have small, anovulatory ovaries with reduced numbers of follicles. Levels of the pituitary hormones luteinizing hormone and prolactin and gonadal steroids are low in these animals. Pituitaries of IRS-2−1 animals are decreased in size and contain reduced numbers of gonadotrophs. Additionally, IRS-2−1 females display increased food intake and develop obesity, despite elevated leptin levels, suggesting abnormalities in hypothalamic function. Coupled with recent observations that brain-specific deletion of the insulin receptor causes a similar phenotype, these findings implicate IRS signalling pathways in the neuroendocrine regulation of reproduction and energy homeostasis.
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Conference Article|
August 01 2001
Insulin receptor substrate proteins and neuroendocrine function
D. J. Withers
D. J. Withers
1
1Department of Metabolic Medicine, ICSM Hammersmith Campus, Du Cane Road, London W12 0NN, U.K.
1e-mail [email protected]
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Publisher: Portland Press Ltd
Received:
March 07 2001
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2001 Biochemical Society
2001
Biochem Soc Trans (2001) 29 (4): 525–529.
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Received:
March 07 2001
Citation
D. J. Withers; Insulin receptor substrate proteins and neuroendocrine function. Biochem Soc Trans 1 August 2001; 29 (4): 525–529. doi: https://doi.org/10.1042/bst0290525
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