The impact of the postmenopausal hormonal milieu on brown fat activity and energy expenditure

绝经后激素环境对棕色脂肪活性和能量消耗的影响

• 批准号: 10470995
• 负责人: Edward L Melanson
• 金额: $ 23.33万
• 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: 2016-09-16 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10470995
• 关键词: Abdomen; Acetates; Acute; Adipose tissue; Affect; Agonist; Animals; Attenuated; Award; Back; Behavioral; Biological Process; Body Composition; Body Weight; Brown Fat; Cell Respiration; Chronic; Chronic Disease; Data; Development; Energy Metabolism; Estradiol; Fatty acid glycerol esters; Follicle Stimulating Hormone; Glucose; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Gonadotropin Releasing Hormone Inhibitor; Gonadotropins; Hormonal; Hormone Antagonists; Hormones; Hour; Image; Impairment; Indirect Calorimetry; Intervention; Investigation; Lead; Light; Lipids; Luteinizing Hormone; Measures; Mediating; Menopause; Metabolic; Metabolic Diseases; Mus; Nonesterified Fatty Acids; Normal Range; Obesity; Organ; Ovarian; Ovariectomy; Pharmacology; Placebos; Population; Positron; Postmenopause; Premenopause; Progesterone; Progestins; Proteins; Research; Rest; Risk; Rodent; Steroidal Estrogen; Strategic Planning; Testing; Thermogenesis; Tissues; Tracer; Triglycerides; United States National Institutes of Health; Visceral; Visceral fat; Weight Gain; Woman; X-Ray Computed Tomography; arm; dietary; glucose uptake; gonad function; obesity risk; placebo group; pre-clinical; prevent; primary outcome; randomized controlled study; reproductive function; response; therapeutically effective; total energy expenditure; transdermal estrogen; treatment arm; uncoupling protein 1

Summary The menopause is associated with an increase in fat mass (FM), particularly visceral fat, increasing the risk of chronic metabolic disease. The loss of ovarian function during the menopause leads to marked decreases in sex steroids (estrogens and progestins) and increases in gonadotropins (e.g., follicular stimulating hormone (FSH)). A mechanism contributing to weight gain with loss of ovarian function is reductions in energy expenditure (EE). We have shown that suppressing ovarian function in premenopausal women reduces resting energy expenditure (REE), and this is prevented by adding back estradiol (E2). In the previous award period, we studied whether ovarian function impacts brown adipose tissue (BAT) and whether reductions in BAT activity contribute to the reductions in REE. We showed that BAT oxidative metabolism is lower in post- than premenopausal women, and that suppressing ovarian function causes marked reductions in BAT oxidative metabolism. These results suggest that E2 modulates BAT activity. However, recent pre-clinical evidence suggests that blocking FSH activity increases REE and BAT activity and decreases FM. Whether E2 and FSH affect BAT activity in postmenopausal women is not known. Active BAT also takes up circulating substrates (e.g., triglycerides) which may confer additional metabolic benefits. In this competing renewal application, we propose to determine the impact of the postmenopausal hormonal milieu on EE, BAT activity, and post-prandial triglycerides. We hypothesize that E2 increases and FSH decreases BAT activity, and that higher levels of BAT activity will be associated with a) higher REE and 24 h EE, and b) lower post-prandial lipids. To test these hypotheses, we will use a gonadotropin releasing hormone antagonist (GnRHANT) and transdermal estrogen (E2) to isolate the effects FSH and E2 on BAT activity in postmenopausal women. Women will be studied before and after 6 months of treatment. The three treatment arms will be GnRHANT + Placebo (PL), GnRHANT + E2, and a double placebo arm. BAT activity will be quantified using dynamic positron emission topography/computed tomography (PET/CT) imaging combined with 11C-acetate and 18flourodeoxyglucose (18FDG) tracers. In both aims, we will also measure REE, 24 h EE, and post-prandial substrates. Studying the E2- and FSH-mediated effects on BAT and EE will increase our understanding of how the loss of ovarian function during the menopausal transition contributes to weight gain and an increase in visceral adipose tissue, increasing the risk of obesity-related chronic diseases. This could lead to development of behavioral or pharmacologic interventions to attenuate decreases in EE and reduce risk for weight gain.

总结 更年期与脂肪量（FM），特别是内脏脂肪的增加有关， 增加慢性代谢疾病的风险。卵巢功能的丧失 绝经导致性类固醇（雌激素和孕激素）显著减少， 促性腺激素的增加（例如，促卵泡激素（FSH））。一种机制 导致体重增加和卵巢功能丧失的是能量消耗（EE）的减少。 我们已经证明，抑制绝经前妇女的卵巢功能， 能量消耗（REE），这是通过补充雌二醇（E2）来防止的。上一 在奖励期间，我们研究了卵巢功能是否影响棕色脂肪组织（BAT）， 最佳可得技术活动的减少是否有助于REE的减少。我们发现BAT 绝经后妇女的氧化代谢低于绝经前妇女， 卵巢功能导致BAT氧化代谢显著降低。这些结果表明 E2调节BAT的活性。然而，最近的临床前证据表明， FSH活性增加REE和BAT活性，降低FM。E2和FSH是否影响 绝经后妇女的BAT活性尚不清楚。活跃的BAT也占据流通 衬底（例如，甘油三酯），其可赋予额外的代谢益处。在这场竞争中， 更新申请，我们建议确定绝经后激素的影响， 环境对EE、BAT活性和餐后甘油三酯的影响。我们假设E2增加 FSH降低BAT活性，较高水平的BAT活性将与a） B）降低餐后血脂。为了验证这些假设，我们将 使用促性腺激素释放激素拮抗剂（GnRHANT）和经皮雌激素（E2）， 分离FSH和E2对绝经后妇女BAT活性的影响。妇女将被 治疗前和治疗后6个月。三个治疗组将为GnRHANT + 安慰剂（PL）、GnRHANT + E2和双安慰剂组。 动态正电子发射断层扫描/计算机断层扫描（PET/CT）成像结合 11 C-乙酸盐和18氟脱氧葡萄糖（18 FDG）示踪剂。在这两个目标中，我们还将测量REE， 24 h EE和餐后底物。研究E2和FSH介导的对BAT的影响， EE将增加我们对绝经期卵巢功能丧失的理解， 过渡有助于体重增加和内脏脂肪组织的增加， 与肥胖相关的慢性疾病的风险。这可能会导致行为或 药物干预以减弱EE降低并降低体重增加的风险。