Metabolic and xenobiotic control of thyroid hormone metabolism

目前的建议集中在甲状腺激素激活（T4到T3的转换）的概念，通过 2型脱碘酶（D2）在燃料稳态和能量消耗中起关键作用。这个概念 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的主要产热组织， 其他小型哺乳动物最近，在人类骨骼肌中发现了D2活性， 相当令人兴奋的是，脱碘是代谢的一种常见机制， 在这种背景下，我们立即对BAT D2在一个细胞中上调的事实感兴趣。 对饮食诱导的肥胖抵抗的小鼠模型。在该模型中，补充0.5%胆汁酸 防止动物在高脂肪饮食中超重或产生胰岛素抵抗。激烈 一项合作研究首次发现了一种不依赖于FXR的代谢途径， 胆汁酸与G蛋白偶联受体TGR 5相互作用，从而刺激D2代谢， 相关组织，包括BAT和人骨骼肌细胞。我们的初步研究表明，其他; GPCR也刺激D2。这些惊人的数据表明，控制D2的代谢物谱， 这种机制起作用靶组织的范围可能比以前更广泛 想的考虑到这一点，我们已经开始寻找新的D2调节物质，并已 初步证据支持异生物质化合物的重要调节作用。了解如何 来自快速波动的内源性分子和异生因子的代谢信号通过以下途径整合： D2途径是这些研究的主要目标。最终，通过了解这些新的机制， 甲状腺激素依赖的代谢控制，我们希望确定新的目标和方法， 代谢紊乱的治疗性干预，包括II型糖尿病、肥胖和代谢紊乱。 综合征

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 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. These striking data suggest 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.