IRS-2 pathways integrate female reproduction and energy homeostasis

Severe dietary restriction, catabolic states and even short-term caloric de privation impair fertility in mammals. Likewise, obesity is associated with infertile conditions such as polycystic ovary syndrome(1,2). The reproduct ive status of lower organisms such as Caenorhabditis elegans is also modula ted by availability of nutrients(3,4). Thus, fertility requires the integra tion of reproductive and metabolic signals. Here we show that deletion of i nsulin receptor substrate-2 (IRS-2), a component of the insulin/insulin-lik e growth factor-1 signalling cascade, causes female infertility. Mice lacki ng IRS-2 have small, anovulatory ovaries with reduced numbers of follicles. Plasma concentrations of luteinizing hormone, prolactin and sex steroids a re low in these animals. Pituitaries are decreased in size and contain redu ced numbers of gonadotrophs. Females lacking IRS-2 have increased food inta ke and obesity, despite elevated levels of leptin. Our findings indicate th at insulin, together with leptin and other neuropeptides, may modulate hypo thalamic control of appetite and reproductive endocrinology. Coupled with f indings on the role of insulin-signalling pathways in the regulation of fer tility, metabolism and longevity in C. elegans and Drosophila(3-5), we have identified an evolutionarily conserved mechanism in mammals that regulates both reproduction and energy homeostasis.