Estradiol Regulation of In Vivo Adipose Tissue Glucocorticoid Metabolism

雌二醇对体内脂肪组织糖皮质激素代谢的调节

• 批准号: 7230053
• 负责人: WENDOLYN S GOZANSKY
• 金额: $ 15.33万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7230053
• 关键词: 11-beta-Hydroxysteroid Dehydrogenase Type 1; 11-beta-Hydroxysteroid Dehydrogenases; Abdomen; Acute; Address; Adipocytes; Adipose tissue; Age; Agonist; Animal Model; Animals; Attenuated; Back; Biological; Biology; Body fat; Central obesity; Condition; Cortisone; Development; Dexamethasone; Dose; Enzymes; Estradiol; Estrogens; Experimental Models; Exploratory/Developmental Grant; Exposure to; Fatty acid glycerol esters; Figs - dietary; Glucocorticoids; Goals; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Gonadotropin Releasing Hormone Inhibitor; Grant; Health; Hormone Antagonists; Hormones; Human; Hydrocortisone; Impaired cognition; Kidney; Knockout Mice; Liver; Measures; Mediating; Menopause; Metabolic; Metabolism; Methodology; Microdialysis; Morbidity - disease rate; Mus; Oral; Osteoporosis; Perimenopause; Peripheral; Phase; Physiological; Placebos; Plasma; Postmenopause; Premenopause; Process; Protein Overexpression; Randomized; Randomized Controlled Clinical Trials; Randomized Controlled Trials; Regulation; Research Personnel; Resistance; Risk; Serum; Simulate; Site; Stimulus; Techniques; Tissues; Translating; Weight Gain; Withdrawal; Woman; abdominal fat; base; body system; day; hormone therapy; hypothalamic pituitary ovarian axis; hypothalamic-pituitary-adrenal axis; in vivo; innovation; men; mortality; novel; programs; proliferative phase Menstrual cycle; reproductive; response; subcutaneous

DESCRIPTION (provided by applicant): Premenopausal women are protected against abdominal obesity and this appears to be estrogen-mediated. Pharmacologic suppression of sex hormones in premenopausal women increases total body fat, with disproportionate increases in trunk fat. Randomized controlled trials provide strong evidence that estrogen-based hormone therapy attenuates weight gain and abdominal fat accumulation in postmenopausal women; the mechanisms for these actions remain unknown. Thus, our global aim is to employ an experimental model to evaluate a potential biological mechanism by which the withdrawal of estradiol (E2) triggers an increase in abdominal adiposity. Glucocorticoids are a potent stimulus of abdominal fat accumulation. In animals, estrogen deficiency increases conversion of the inactive glucocorticoid, cortisone, to the active glucocorticoid, cortisol, thereby amplifying tissue exposure to cortisol; this action is mediated by the enzyme 11-beta-hydroxysteroid dehydrogenase type 1. We propose to study both whole-body and abdominal adipose tissue-specific (using a novel in vivo microdialysis technique) glucocorticoid metabolism in 30 healthy, premenopausal women after 5 days of sex hormone suppression (GnRH antagonist (GnRHant)). To isolate the effect of E2, we will continue GnRHant and randomize women to 5 days of "add-back" therapy with low-or high-dose transdermal E2 or placebo. We hypothesize that sex hormone suppression will increase both whole body and subcutaneous abdominal fat conversion of cortisone to cortisol compared with the early and late follicular menstrual cycle phases (expected dose response: GnRHant > early follicular > late follicular). Further, we postulate that E2 add-back will reverse the effects of sex hormone suppression. Our studies will evaluate a biological mechanism that we believe is responsible for the menopausal increase in abdominal adiposity and its associated metabolic sequelae. Importantly, the mechanism that we will study, E2-mediated regulation of glucocorticoid metabolism, likely has relevance to other conditions that also increase after the menopause transition (e.g., osteoporosis, cognitive impairment). Therefore, this proposal is highly responsive to the RFA goal of addressing the underlying biology of endogenous hypothalamic-pituitary-ovarian axis hormones and their interactions with non-reproductive organ systems.

描述(由申请人提供)：绝经前的妇女受到保护，防止腹部肥胖，这似乎是由雌激素介导的。药物抑制绝经前妇女的性激素增加了全身脂肪，其中躯干脂肪不成比例地增加。随机对照试验提供了强有力的证据表明，基于雌激素的激素治疗可以减轻绝经后妇女的体重增加和腹部脂肪堆积；这些作用的机制尚不清楚。因此，我们的全球目标是使用一个实验模型来评估雌激素(E2)的退出触发腹部肥胖症增加的潜在生物学机制。糖皮质激素是腹部脂肪堆积的有力刺激因素。在动物中，雌激素缺乏会增加不活跃的糖皮质激素皮质醇的转化，从而扩大组织对皮质醇的暴露；这一作用是由酶11-β-羟基类固醇脱氢酶1介导的。我们建议研究30名健康的绝经前妇女在性激素抑制5天后的全身和腹部脂肪组织特异性(使用一种新的体内微透析技术)糖皮质激素的代谢。为了分离E2的作用，我们将继续使用GnRHant，并随机对女性进行为期5天的“加回”治疗，使用低剂量或高剂量的经皮雌二醇或安慰剂。我们假设，与卵泡月经周期的早期和晚期相比，性激素抑制将增加全身和皮下腹部脂肪将皮质醇转化为皮质醇(预期剂量反应：GnRHant&GT；早期卵泡&GT；晚期卵泡)。此外，我们假设E2的增加将逆转性激素抑制的效果。我们的研究将评估一种生物学机制，我们认为这是绝经后腹部肥胖症增加及其相关代谢后遗症的原因。重要的是，我们将要研究的机制，即E2介导的糖皮质激素代谢调节，可能与绝经后也会增加的其他情况相关(例如，骨质疏松症、认知障碍)。因此，该建议高度响应了RFA的目标，即解决内源性下丘脑-垂体-卵巢轴激素及其与非生殖器官系统的相互作用的潜在生物学问题。