Metabolic and xenobiotic control of thyroid hormone metabolism

描述(由申请人提供)：目前的提案集中在通过2型脱碘酶(D2)激活甲状腺激素(T4到T3)在燃料动态平衡和能量消耗中发挥关键作用的概念。这一概念源于对棕色脂肪组织(BAT)的研究，BAT是人类新生儿和其他小型哺乳动物的主要产热组织。最近，人类骨骼肌中D2活性的发现引起了相当大的兴奋，因为人们已经清楚地知道，去碘是代谢控制的一种常见机制。鉴于这一背景，我们立即对BAT D2在饮食诱导肥胖抵抗的小鼠模型中上调的事实感兴趣。在这个模型中，补充0.5%的胆汁酸可以防止动物在摄入高脂肪食物时变得超重或出现胰岛素抵抗。密集的合作研究首次认识到胆汁酸与G蛋白偶联受体TGR5相互作用，从而在代谢相关组织(包括BAT和人类骨骼肌细胞)中刺激D2的FXR非依赖性代谢途径。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的代谢物的光谱，以及这一机制发挥作用的靶组织的范围可能比之前认为的更广泛。考虑到这一点，我们已经开始寻找新的D2调节物质，并有初步证据支持对外源化合物的显著调节作用。了解来自快速波动的内源分子和外源因子的代谢信号如何通过D2途径整合是这些研究的主要目标。最终，通过了解这些甲状腺激素依赖的代谢控制的新机制，我们希望为包括II型糖尿病、肥胖和代谢综合征在内的代谢疾病的治疗干预确定新的靶点和方法。

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.