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

项目摘要 人类棕色脂肪组织的生理相关性在很大程度上是未知的。我们已经证明 抑制绝经前妇女的卵巢功能可降低静息能量消耗（REE），这是 通过补充雌二醇（E2）来预防。我们的初步数据表明，这可能是由于，部分， 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的功能和产热活性由E2调节。然而，E2状态是否影响BAT活性， 女性没有被研究过。我们的首要假设是，人体中的BAT活动是由E2调节的。在 本研究将研究1）在基础（室温）和激发条件下BAT对REE的贡献 条件（轻度冷暴露）;以及2）这些反应是否受E2状态调节。以确定是否 内源性E2的自然下降有助于BAT活性的变化，我们将比较前 和绝经后妇女。我们还将探讨是否抑制卵巢激素在前， 绝经期妇女损害BAT活性。将使用动态正电子发射对BAT活动进行量化 拓扑/计算机断层扫描（PET/CT）成像与11 C-乙酸盐示踪剂组合。我们将评估 BAT的产热反应，通过测量REE、寒战、皮肤和核心的冷诱导变化 温度拟议的研究与RFA-DK-15-031的两个主要目标一致， 这是1）探索BAT在人类中的生物学功能; 2）确定调节的条件 它在人类中的活动。研究E2对BAT和REE的介导作用将增加我们对E2如何影响BAT和REE的理解。 绝经过渡期卵巢功能的丧失导致体重增加， 内脏脂肪组织，增加与肥胖有关的慢性疾病的风险。这可能导致发展 行为或药物干预，以减弱REE的下降，降低体重增加的风险。

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.