Metabolic and xenobiotic control of thyroid hormone metabolism

描述（由申请人提供）：当前提案的重点是通过2型脱碘酶（D2）激活甲状腺激素（T4至T3转化）在燃料稳态和能量消耗中起关键作用的概念。这一概念起源于对棕色脂肪组织（BAT）的研究，棕色脂肪组织是人类新生儿和其他小型哺乳动物的主要产热组织。最近，在人类骨骼肌中发现D2活性引起了相当大的兴奋，因为已经清楚脱碘是代谢控制的常见机制（1）。在这种背景下，我们立即对BAT D2在对饮食诱导的肥胖具有抵抗力的小鼠模型中上调的事实感兴趣。在该模型中，补充0.5%胆汁酸可防止动物在高脂肪饮食中超重或胰岛素抵抗。通过深入的合作研究，首次发现了一种不依赖于FXR的代谢途径，胆汁酸通过该途径与G蛋白偶联受体TGR 5相互作用，从而刺激代谢相关组织（包括BAT和人骨骼肌细胞）中的D2。我们的初步研究表明，其他GPCR也刺激D2。这一惊人的数据表明，控制D2的代谢物谱以及该机制起作用的靶组织范围可能比以前认为的更广泛。考虑到这一点，我们已经开始寻找新的D2调节物质，并有初步证据支持显着的调节作用的异生物质化合物。这些研究的主要目标是了解来自快速波动的内源性分子和外源性因子的代谢信号如何通过D2途径整合。最终，通过了解这些甲状腺激素依赖性代谢控制的新机制，我们希望确定新的靶点和方法，用于治疗包括II型糖尿病、肥胖和代谢综合征在内的代谢紊乱。

DESCRIPTION (provided by applicant): The current proposal focuses on the concept that thyroid hormone activation (T4 to T3 conversion) via the type 2 deiodinase (D2) plays a critical role in fuel homeostasis and energy expenditure. This concept originated from studies in brown adipose tissue (BAT), the main thermogenic tissue in human newborns and other small mammals. Recently, the discovery of D2 activity in human skeletal muscle has generated considerable excitement as it has become clear that deiodination is a common mechanism for metabolic control (1). Given this background, we were immediately intrigued by the fact that BAT D2 is up-regulated in a mouse model of resistance to diet-induced obesity. In this model, supplementation with 0.5% bile acids prevents animals from becoming overweight or insulin-resistant when placed on a high fat diet. Intense collaborative investigation resulted in the first recognition of an FXR-independent metabolic pathway through which bile acids interact with the G-protein coupled receptor TGR5 and thus stimulate D2 in metabolically relevant tissues including BAT and human skeletal myocytes. Our preliminary studies indicate that other GPCRs also stimulate D2. This striking data suggests that the spectrum of metabolites controlling D2, and the range of target tissues in which this mechanism is operant may be even more extensive than previously thought. With this in mind, we have begun to search for novel D2-regulating substances, and have preliminary evidence supporting significant regulatory effects for xenobiotic compounds. Understanding how metabolic signals from rapidly fluctuating endogenous molecules and xenobiotic factors are integrated via the D2 pathway is the major goal of these studies. Ultimately, by understanding these novel mechanisms for thyroid-hormone dependent metabolic control, we hope to identify new targets and approaches for therapeutic intervention in metabolic disorders including type II diabetes, obesity, and the metabolic syndrome.