Reprometabolic Syndrome Mediates Subfertility in Obesity

生殖代谢综合征介导肥胖导致的生育能力低下

• 批准号: 9269600
• 负责人: Nanette F. Santoro
• 金额: $ 30.94万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-04 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269600
• 关键词: Acute; Adverse effects; Anti-Inflammatory Agents; Anti-inflammatory; Barker Hypothesis; Behavior Therapy; Body Weight decreased; Cardiovascular Diseases; Characteristics; Chronic; Clinical; Closure by clamp; Conceptions; Development; Diabetes Mellitus; Diet; Dietary Intervention; Dose; Estradiol; Euglycemic Clamping; Excretory function; Fatty Acids; Fatty acid glycerol esters; Functional disorder; GNRH1 gene; Gonadal Steroid Hormones; Gonadotropins; High Fat Diet; Hormonal; Hormones; Hyperinsulinism; Hyperlipidemia; Hypogonadotropism; Inflammation; Inflammatory; Infusion procedures; Insulin; Insulin Resistance; Intervention; Investigation; Klinefelter' s Syndrome; Link; Lipids; Lipolysis; Measures; Mediating; Mediation; Menstrual cycle; Metabolic; Methods; Modeling; Monitor; Names; Nonesterified Fatty Acids; Obesity; Omega-3 Fatty Acids; Omega-6 Fatty Acids; Operative Surgical Procedures; Outcome; Pattern; Phenotype; Pituitary Gland; Play; Pregnancy; Pregnancy Complications; Prevention; Production; Progesterone; Role; Signal Transduction; Site; Syndrome; Testing; Weight; Woman; Work; cytokine; design; experimental study; feeding; glucose uptake; inflammatory marker; inflammatory milieu; insulin mediators; lipid mediator; men; offspring; public health relevance; reproductive; reproductive hormone; response; success; transmission process; urinary

 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.

 描述（由申请人提供）：肥胖在受孕和怀孕的每个阶段都发挥着不利作用，越来越多的证据表明，性腺功能相对低下，月经周期激素分泌减少可能是导致生育力低下表型的原因，也可能是导致妊娠和发育并发症的原因。我们和其他人已经记录了 LH、FSH、雌二醇和雌二醇代谢物以及黄体酮的减少。与正常体重的女性相比，肥胖女性的黄体酮代谢水平随着手术减肥而部分逆转。我们的初步研究结果表明，我们可以通过手术减肥来逆转垂体。与我们通过快速输注游离脂肪酸和胰岛素（但不是单独使用任何一种药物）在肥胖女性中观察到的情况相似，会导致正常体重女性垂体产生 LH 和 FSH 缺陷。所提出的实验旨在检验这样的假设：过量的游离脂肪酸和胰岛素的结合（通常发生在肥胖症中）将至少部分地重现正常体重女性（NWW）的肥胖生殖表型，我们将这种表型命名为。 “再代谢综合征”具体目标 1 预测，在短期内联合使用胰岛素和脂肪酸输注，可以在正常体重女性中可靠地重建高保真再代谢综合征模型，以及如果给予长期的 为期一个月的正常高脂肪饮食 (HFD) 将在急性脂质和胰岛素输注之前和之后进行评估，或者长达一个月的 HFD 喂养将通过以下方式量化胰岛素抵抗的诱导如何导致再代谢综合征。在 HFD 干预之前和之后进行两阶段正常血糖胰岛素钳夹检查期间的葡萄糖摄取和脂肪分解，并将生殖激素的变化与胰岛素的具体作用联系起来，将确定目标 3 的关键变化。炎症标志物与再代谢综合征一起诱导，以识别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。