The impact of estrogen status on the biological function of brown adipose tissue in women measured using quantitative PET/CT

使用定量 PET/CT 测量雌激素状态对女性棕色脂肪组织生物学功能的影响

• 批准号: 9353399
• 负责人: Edward L Melanson
• 金额: $ 58.96万
• 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 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9353399
• 关键词: Acetates; Acute; Adipose tissue; Affect; Agonist; Attenuated; Back; Behavioral; Biological Process; Body Composition; Body Weight; Brown Fat; Cell Respiration; Chronic Disease; Data; Deoxyglucose; Development; Energy Metabolism; Estradiol; Estrogens; Fatty acid glycerol esters; Female; Gender Role; Goals; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Human; Image; Impairment; Intervention; Lead; Luteal Phase; Measures; Mediating; Menopause; Menstrual cycle; Metabolic; Metabolic Clearance Rate; Obesity; Obesity associated disease; Ovarian; Ovarian Ablation; Ovarian hormone; Pharmacology; Phase; Physiological; Population; Positron; Positron-Emission Tomography; Postmenopause; Premenopause; Research; Rest; Risk; Rodent; Role; Series; Serum; Shivering; Skin; Steroids; Stimulus; Strategic Planning; Support System; Sympathetic Nervous System; Temperature; Thermogenesis; Tracer; Treatment Efficacy; United States National Institutes of Health; Visceral; Weight Gain; Woman; Women' s Role; X-Ray Computed Tomography; energy balance; in vivo; men; obesity risk; preclinical study; prevent; response; time interval; uptake

Project Summary The physiological relevance of brown adipose tissue in humans is largely unknown. We have shown that suppressing ovarian function in premenopausal women reduces resting energy expenditure (REE), and this is prevented by adding back estradiol (E2). Our preliminary data suggest that this may be due, in part, to reduced brown adipose tissue (BAT) activity. There is also compelling evidence from basic and pre-clinical studies that BAT function and thermogenic activity is modulated by E2. However, whether E2 status affects BAT activity in women has not been studied. Our overarching hypothesis is that BAT activity in humans is modulated by E2. In this research, we will study 1) the contribution of BAT to REE under basal (room temperature) and stimulated conditions (mild cold-exposure); and 2) whether these responses are modulated by E2 status. To determine if natural declines in endogenous E2 contribute to changes in BAT activity, we will compare BAT activity in pre- and post-menopausal women. We will also explore whether suppression of ovarian hormones in pre- menopausal women impairs BAT activity. BAT activity will be quantified using dynamic positron emission topography/computed tomography (PET/CT) imaging combined with 11C-acetate tracers. We will assess the thermogenic response of BAT by measuring cold-induced changes in REE, shivering, and skin and core temperature. The proposed research is well-aligned with two of the primary objectives of RFA-DK-15-031, which are 1) to explore the biological functions of BAT in humans; and 2) determine conditions that modulate its activity in humans. Studying E2-mediated effects on BAT and REE 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 REE and reduce risk for weight gain.

项目概要 人类棕色脂肪组织的生理相关性在很大程度上尚不清楚。我们已经证明 抑制绝经前女性的卵巢功能会减少静息能量消耗（REE），这是 通过添加回雌二醇（E2）来预防。我们的初步数据表明，这可能部分是由于减少 棕色脂肪组织（BAT）活性。基础和临床前研究也有令人信服的证据表明 BAT 功能和生热活性受 E2 调节。然而，E2 状态是否会影响 BAT 活动 女性尚未被研究。我们的首要假设是人类 BAT 活性受 E2 调节。在 在这项研究中，我们将研究 1) 在基础（室温）和刺激下 BAT 对 REE 的贡献 条件（轻度冷暴露）； 2) 这些响应是否受 E2 状态的调节。确定是否 内源性 E2 的自然下降会导致 BAT 活性的变化，我们将比较之前的 BAT 活性 和绝经后妇女。我们还将探讨卵巢激素的抑制是否在预 更年期妇女会损害 BAT 活性。 BAT 活动将使用动态正电子发射进行量化 地形图/计算机断层扫描 (PET/CT) 成像与 11C-乙酸示踪剂相结合。我们将评估 通过测量寒冷引起的 REE、颤抖以及皮肤和核心的变化来确定 BAT 的生热反应 温度。拟议的研究与 RFA-DK-15-031 的两个主要目标非常一致， 1）探索BAT在人体中的生物学功能； 2) 确定调节条件 它在人类中的活动。研究 E2 介导的 BAT 和 REE 影响将增加我们对如何影响的理解 绝经过渡期间卵巢功能的丧失会导致体重增加和 内脏脂肪组织，增加患肥胖相关慢性疾病的风险。这可能会导致发展 行为或药物干预措施，以减轻 REE 的减少并降低体重增加的风险。