Polycystic ovarian syndrome (PCOS) is a reproductive and metabolic disorder that occurs in 5-10% of premenopausal women, often producing infertility and increased risk of metabolic and cardiovascular disease. The combined evidence obtained by our SCOR investigators strongly supports our central hypothesis that PCOS has a genetic basis linked to excess androgen production, and that the androgen excess in the intrauterine environment programs the pathogenesis of the disorder. Our animal studies have provided further support for this hypothesis, showing that prenatal androgen exposure can program the development of PCOS-like phenotypic traits in rats and mice. The proposed experiments are designed to determine the mechanisms by which prenatal androgen exposure may program two of the most clinically important of these patho physio logical traits: hepatic insulin resistance and visceral adiposity. We have determined that prenatal androgenization (PNA) produces reproductive dysfunction in adulthood by programming resistance to several classic actions of estrogen (E2) in the brain. Estrogen was also found to induce expression of ATP sensitive potassium channel (KATp) subunit genes in hypothalamus;these channels 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 hypothalamic action. We have therefore proposed the novel hypothesis that PNA programs development of hepatic insulin resistance and visceral adiposity by altering functional development of hypothalamic-autonomic control circuitries, rendering them resistant to regulation by E2, and hence depleted of KATp channels and compromised in their ability to regulate hepatic insulin sensitivity. To test this hypothesis, we will first determine if PNA programs reduced hypothalamic KATP channel expression and reduced hepatic responsiveness to hypothalamic KATP channel activation (Aim 1). We will then assess whether PNA programs 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 and visceral adiposity by a hypothalamic action will then be assessed (Aim 4), using local infusions of E2 in the brain as well as a novel neuron-specific estrogen receptor-a knockout (NERKO) mouse to differentiate hypothalamic versus peripheral actions of E2. Finally, we will test whether PNA blocks E2 effects on these metabolic parameters in adulthood. These studies will provide important new information on mechanisms by which intrauterine androgen exposure programs metabolic pathophysiologies in adulthood, and may thus provide major new insights into the pathogenesis of metabolic dysfunction in PCOS women.
NIH ExPorter
NIH ExPorter