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.

 说明(申请人提供)：肥胖在受孕和怀孕的每个阶段都扮演着不利的角色，越来越多的证据表明，相对的性腺激素低促性腺功能低下症，以及月经周期激素分泌减少，可能是导致亚生育表型的因素，也可能是妊娠并发症和成人疾病(如糖尿病和心血管疾病)的发育根源的因素。我们和其他人已经证明，与正常体重的女性相比，肥胖女性的黄体生成素、卵泡刺激素、雌二醇和雌二醇代谢物以及孕酮和孕酮代谢物减少。通过手术减肥，这种相对的低促性腺激素减退症部分逆转。最近，我们发现脑下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，我们可以通过急性注射游离脂肪酸和胰岛素(但不是两种药物中的任何一种)，在正常体重的女性中诱导脑下垂体产生黄体生成素和卵泡刺激素的缺陷，这与我们在肥胖女性中观察到的情况类似。所提出的实验旨在检验这样一种假设，即在肥胖中通常会出现的游离脂肪酸和胰岛素的组合过剩，将至少部分概括正常体重女性(NWW)肥胖的重复表型。我们将这种表型命名为‘再生代谢综合征’。特殊目的1预测，在短期和长期内，使用胰岛素和脂肪酸注射的组合，可以在正常体重的女性身上可靠地重建高保真的再生代谢综合征模型，如果给予它们的话。 一个月的高脂饮食(HFD)。在急性输注脂肪和胰岛素之前和之后或最多一个月的HFD喂养之前和之后，将评估生殖激素。目的2将通过检测在HFD干预前后给予两个阶段的正常血糖胰岛素钳夹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特定作用联系起来，来量化胰岛素抵抗的诱导对再代谢综合征的影响。目的3将确定与再代谢综合征一起诱导的炎性标志物的关键变化，以确定单纯性肥胖患者中与胰岛素和脂质相关的垂体腺抑制的潜在介体。