Editors' ChoicePhysiology

Insulin on the Brain

Science's STKE  26 Sep 2000:
Vol. 2000, Issue 51, pp. tw3
DOI: 10.1126/stke.2000.51.tw3

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]