IRS-2 pathways integrate female reproduction and energy homeostasis

Deborah J. Burks, Jaime Font de Mora, Markus Schubert, Dominic J. Withers, Martin G. Myers, Heather H. Towery, Shari L. Altamuro, Carrie L. Flint and Morris F. White ()
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Deborah J. Burks: Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School
Jaime Font de Mora: Centro de Investigacion del Cancer, Facultad de Medicina, Universidad de Salamanca
Markus Schubert: Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School
Dominic J. Withers: Imperial College School of Medicine, Hammersmith Campus
Martin G. Myers: Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School
Heather H. Towery: Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School
Shari L. Altamuro: Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School
Carrie L. Flint: Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School
Morris F. White: Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School

Nature, 2000, vol. 407, issue 6802, 377-382

Abstract: Abstract Severe dietary restriction, catabolic states and even short-term caloric deprivation impair fertility in mammals. Likewise, obesity is associated with infertile conditions such as polycystic ovary syndrome1,2. The reproductive status of lower organisms such as Caenorhabditis elegans is also modulated by availability of nutrients3,4. Thus, fertility requires the integration of reproductive and metabolic signals. Here we show that deletion of insulin receptor substrate-2 (IRS-2), a component of the insulin/insulin-like growth factor-1 signalling cascade, causes female infertility. Mice lacking IRS-2 have small, anovulatory ovaries with reduced numbers of follicles. Plasma concentrations of luteinizing hormone, prolactin and sex steroids are low in these animals. Pituitaries are decreased in size and contain reduced numbers of gonadotrophs. Females lacking IRS-2 have increased food intake and obesity, despite elevated levels of leptin. Our findings indicate that insulin, together with leptin and other neuropeptides, may modulate hypothalamic control of appetite and reproductive endocrinology. Coupled with findings on the role of insulin-signalling pathways in the regulation of fertility, metabolism and longevity in C. elegans and Drosophila3,4,5, we have identified an evolutionarily conserved mechanism in mammals that regulates both reproduction and energy homeostasis.

Date: 2000
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DOI: 10.1038/35030105

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