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IRS-2 pathways integrate female reproduction and energy homeostasis

Nature volume 407, pages 377–382 (2000)Cite this article

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.

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Figure 1: Reproductive and metabolic characteristics of IRS-2-deficient animals.
Figure 2: Ovarian phenotype of the IRS-2 knockout.
Figure 3: Reproductive hormone levels and response of ovariectomized mice to exogenous sex steroid stimulation.
Figure 4: Pituitary phenotype of IRS-2-/- females.
Figure 5: Analysis of feeding and energy homeostasis.

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Acknowledgements

We are grateful to C. Cahill for preparation of pituitary sections; A. Parlow for antibodies to pituitary hormones; A. Dunaif for testosterone measurements; and D. Hess for helpful discussions of murine sex hormones.

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Author notes

  1. Dominic J. Withers

    Present address: Department of Metabolic Medicine, Imperial College School of Medicine, Hammersmith Campus, DuCane Road, London, W12 ONN, UK

Authors and Affiliations

  1. Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, One Joslin Place , Boston, 02215, Massachusetts, USA

    Deborah J. Burks, Markus Schubert, Martin G. Myers, Heather H. Towery, Shari L. Altamuro, Carrie L. Flint & Morris F. White

  2. Centro de Investigacion del Cancer, Facultad de Medicina, Universidad de Salamanca, Salamanca, 37007, Spain

    Jaime Font de Mora

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Correspondence to Morris F. White.

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Burks, D., de Mora, J., Schubert, M. et al. IRS-2 pathways integrate female reproduction and energy homeostasis. Nature 407, 377–382 (2000). https://doi.org/10.1038/35030105

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