Reprometabolic Syndrome Mediates Subfertility in Obesity

 描述（由申请方提供）：肥胖在受孕和妊娠的每个阶段都起着不利作用，越来越多的证据表明，相对低促性腺激素性功能减退症和月经周期激素分泌减少可能导致生育力低下表型，并可能导致妊娠并发症和成人疾病（如糖尿病和心血管疾病）的发育起源。我们和其他研究者已经证实，与正常体重的女性相比，肥胖女性的LH、FSH、雌二醇和雌二醇代谢产物以及孕酮和孕酮代谢产物减少。这种相对低促性腺激素性性腺功能减退症可通过手术减肥部分逆转。最近，我们已经确定脑垂体是肥胖症患者生殖轴功能缺陷的部位。我们的初步研究结果表明，我们可以诱导正常体重妇女的垂体LH和FSH的产生缺陷，类似于我们在肥胖妇女中观察到的情况，通过急性输注游离脂肪酸和胰岛素（但不能单独使用任何一种药物）。所提出的实验旨在检验这样一种假设，即通常发生在肥胖症中的游离脂肪酸和胰岛素的组合过量将至少部分地再现正常体重女性（NWW）中肥胖症的生殖表型。我们将这种表型命名为“生殖代谢综合征”。具体目标1预测，在正常体重的女性中，短期内使用胰岛素和脂肪酸输注的组合，可以可靠地重建生殖代谢综合征的高保真模型，如果给予长期胰岛素和脂肪酸输注，则可以重建生殖代谢综合征的高保真模型。 一个月的高热量饮食（HFD）。将在急性脂质和胰岛素输注前后或长达一个月的HFD喂养前后评估生殖激素。目的2将通过在HFD干预前后进行两阶段正常血糖胰岛素钳夹期间检查葡萄糖摄取和脂解，并将生殖激素变化与胰岛素的特定作用联系起来，量化胰岛素抵抗的诱导如何导致生殖代谢综合征。目的3将确定沿着生殖代谢综合征诱导的炎症标志物的关键变化，以确定在单纯性肥胖中观察到的胰岛素和脂质相关垂体抑制的潜在介质。

 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.