Insulin receptor substrate proteins and neuroendocrine function

A family of insulin receptor substrate (IRS) proteins mediates the pleiotro pic effects of insulin and insulin-like growth factor 1 (IGF-1) on cellular function by recruiting several intracellular signalling networks. Conventi onal murine knockout strategies have started to reveal distinct physiologic al roles for the IRS proteins. Deletion of Irs1 produces a mild metabolic p henotype with compensated insulin resistance but also causes marked growth retardation. In contrast, mice lacking IRS-2 display nearly normal growth b ut develop diabetes owing to a combination of peripheral insulin resistance and beta -cell failure. As well as the classical metabolic events regulate d by insulin signalling pathways, studies in lower organisms have implicate d insulin/IGF-1 signalling pathways in the control of food intake and repro ductive function. Our analysis of IRS-2 knockout mice shows that female mic e are infertile owing to defects in the hypothalamus, pituitary and gonad. IRS-2(-.-) mice have small, anovulatory ovaries with reduced numbers of fol licles. Levels of the pituitary hormones luteinizing hormone and prolactin and gonadal steroids are low in these animals. Pituitaries of IRS-2(-.-) an imals are decreased in size and contain reduced numbers of gonadotrophs. Ad ditionally, IRS-2(--) females display increased food intake and develop obe sity, despite elevated leptin levels, suggesting abnormalities in hypothala mic function. Coupled with recent observations that brain-specific deletion of the insulin receptor causes a similar phenotype, these findings implica te IRS signalling pathways in the neuroendocrine regulation of reproduction and energy homeostasis.