Reprometabolic Syndrome Mediates Subfertility in Obesity

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 DESCRIPTION (provided by applicant): Obesity plays an adverse role at every stage of conception and pregnancy and mounting evidence implicates relative hypogonadotropic hypogonadism, and reduced menstrual cycle hormone secretion as likely contributors to the subfertility phenotype and possible contributors to complications of pregnancy and the developmental origin of adult diseases such as diabetes and cardiovascular disease. We and others have documented reduced LH, FSH, estradiol and estradiol metabolites and progesterone and progesterone metabolites in obese women compared to those of normal weight. This relative hypogonadotropic hypogonadism partially reverses with surgical weight loss. More recently, we have identified the pituitary gland as a site of defective reproductive axi function in obesity. Our prelminary findings indicate that we can induce deficits in pituitary production of LH and FSH in normal weight women similar to those we have observed in obese women by acutely infusing free fatty acids and insulin (but not either agent alone). The experiments proposed are designed to test the hypothesis that combined excess of free fatty acids and insulin, as typically occurs in obesity, will, at least in part, recapitulate the reprodutive phenotype of obesity in normal weight women (NWW). We have named this phenotype the `reprometabolic syndrome'. Specific Aim 1 predicts that a high- fidelity model of the reprometabolic syndrome can be reliably recreated in normal weight women using a combination of insulin and fatty acid infusion over the short term, and long-term if they are given a eucaloric, high fat diet (HFD) for one month. Reproductive hormones will be assessed before and after acute lipid and insulin infusion or up to one month of HFD feeding. Aim 2 will quantify how induction of insulin resistance contributes to the reprometabolic syndrome by examining glucose uptake and lipolysis during a two-stage euglycemic insulin clamp administered before and after the HFD intervention and linking the reproductive hormone changes to the specific actions of insulin. Aim 3 will determine key changes in inflammatory markers induced along with the reprometabolic syndrome to identify potential mediators of the insulin and lipid related pituitary suppression seen in simple obesity.