The hormone insulin controls the metabolism of glucose, fats, and proteins. Alterations in insulin production and response can lead to type II diabetes, a disorder that affects more than 100 million people worldwide. A growing body of evidence has suggested that insulin signaling may also play an important role in the central nervous system. Brüning et al . have separated the brain action of insulin from its other actions by creating mice that are selectively deficient in the brain insulin receptor. Mutant mice showed modest diet-induced obesity and insulin resistance, as well as a significant reduction in fertility, the latter attributable to impaired hypothalamic regulation of luteinizing hormone. These findings may enhance understanding of the complex metabolic disorders often associated with type II diabetes. A Perspective by Schwartz discusses the data in greater detail. The insulin receptor substrate (IRS)-1 and -2 proteins are expressed in many organs. Burks et al . observed that female IRS-2-deficient mice were infertile, and their ovaries were smaller and had fewer surface follicles. IRS-1 signaling, as measured by tyrosine phosphorylation, appeared normal, suggesting that the ovarian abnormality arose from the absence of IRS-2. Female murine pituitaries were also smaller, and it was suggested that insulin signals in the neuroendocrine axis are disrupted. Additionally, IRS-2-deficient mice had higher leptin levels and defective activation of STAT3, which correlated with increased body fat. Thus, IRS-2 may play a role in the coordinate regulation of reproduction and feeding behavior through the hypothalamic-pituitary-ovary axis. Brüning, J.C., Gautam, D., Burks, D.J., Gillette, J., Schubert, M., Orban, P.C., Klein, R., Krone, W., Müller-Wieland, D., and Kahn, C.R. (2000) Role of brain insulin receptor in control of body weight and reproduction. Science 289 : 2122-2125. [Abstract] [Full Text] Schwartz, M.W. (2000) Staying slim with insulin in mind. Science 289 : 2066-2067. [Full Text] Burks, D.J., Font de Mora, J., Schubert, M., Withers, D.J., Myers, M.G., Towery, H.H., Altamuro, S.L., Flint, C.L., and White, M.F. (2000) IRS-2 pathways integrate female reproduction and energy homeostasis. Nature 407 : 377-382. [Online Journal]