Reproduction is very energy expensive. The energy requirement for a pregnancy is estimated at 160,000 Real with an additional 500-1000 kcal/day for lactation. Because of this requirement, it is likely that mechanisms have evolved to suppress reproduction under periods of famine. Our goal is to understand the integration of metabolism in the regulation of fertility and how abnormalities in metabolic homeostasis, both over and under-nutrition, can lead to infertility. The adipose-derived peptide hormone adiponectin, the longevity-associated protein SirT1, and the PPARy receptor all intersect to regulate insulin sensitivity and exert multiple biological effects in various tissues. Therefore, the role of these proteins in controlling GnRH and gonadotropin gene expression, synthesis, secretion, and fertility in the insulin-resistant prenatal androgenized mouse will be addressed utilizing a combined in vivo and in vitro approach. In the first specific aim, we will test the hypothesis that SirT1 and adiponectin suppress the central HPG axis during times of nutritional deprivation. This will be tested using tissue-specific SirT1 knockouts and transgenics in the brain and pituitary gonadotrope, and adiponectin null mice. In the second specific aim, we will test the hypothesis that a high fat diet increases inflammatory signaling in the hypothalamus and pituitary leading to dysregulation of gonadotropin secretion, and that PPARy suppresses inflammatory signaling to normalize LH levels. This will be tested using tissue-specific deletion of the PPARy receptor in gonadotropes or in the whole brain to identify the site of PPARy action. In the third specific aim, we will test the hypothesis that the prenatally androgenized mouse has increased tissue inflammation that contributes to the insulin resistance. We will determine the site of insulin resistance and will test whether improving insulin resistance rescues the infertility in these mice.
Each aim will feature a series of in vivo animal studies paired with a complementary series of in vitro experiments to elucidate molecular mechanisms.

Public Health Relevance

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 5-10% of women of reproductive age and is the major cause of anovulation and infertility. It is characterized by amenorrhea or oligomenorrhea, multiple ovarian cysts, hyperandrogenemia, hirsutism, and insulin resistance. Women with PCOS are at elevated risk of developing type 2 diabetes, hypertension, atherosclerosis, and dyslipidemia.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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University of California San Diego
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