Polycystic ovarian syndrome (PCOS) is a reproductive and metabolic disorder that occurs in 5-10% ofpremenopausal women, often producing infertility and increased risk of metabolic and cardiovasculardisease. The combined evidence obtained by our SCOR investigators strongly supports our centralhypothesis that PCOS has a genetic basis linked to excess androgen production, and that the androgenexcess in the intrauterine environment programs the pathogenesis of the disorder. Our animal studies haveprovided further support for this hypothesis, showing that prenatal androgen exposure can program thedevelopment of PCOS-like phenotypic traits in rats and mice. The proposed experiments are designed todetermine the mechanisms by which prenatal androgen exposure may program two of the most clinicallyimportant of these patho physio logical traits: hepatic insulin resistance and visceral adiposity.We have determined that prenatal androgenization (PNA) produces reproductive dysfunction in adulthood byprogramming resistance to several classic actions of estrogen (E2) in the brain. Estrogen was also found toinduce expression of ATP sensitive potassium channel (KATp) subunit genes in hypothalamus; thesechannels have been shown to be critically important in the neural control of hepatic insulin sensitivity.Estrogen has also been shown to promote subcutaneous vs. visceral fat deposition by a hypothalamicaction. We have therefore proposed the novel hypothesis that PNA programs development of hepatic insulinresistance and visceral adiposity by altering functional development of hypothalamic-autonomic controlcircuitries, rendering them resistant to regulation by E2, and hence depleted of KATp channels andcompromised in their ability to regulate hepatic insulin sensitivity. To test this hypothesis, we will firstdetermine if PNA programs reduced hypothalamic KATP channel expression and reduced hepaticresponsiveness to hypothalamic KATP channel activation (Aim 1). We will then assess whether PNAprograms impaired responsiveness of hypothalamic neurons to metabolic (Aim 2) and endocrine (Aim 3)signals that regulate hepatic insulin sensitivity. The ability of E2 to regulate hepatic insulin sensitivity andvisceral adiposity by a hypothalamic action will then be assessed (Aim 4), using local infusions of E2 in thebrain as well as a novel neuron-specific estrogen receptor-a knockout (NERKO) mouse to differentiatehypothalamic versus peripheral actions of E2. Finally, we will test whether PNA blocks E2 effects on thesemetabolic parameters in adulthood. These studies will provide important new information on mechanisms bywhich intrauterine androgen exposure programs metabolic pathophysiologies in adulthood, and may thusprovide major new insights into the pathogenesis of metabolic dysfunction in PCOS women.
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