Metabolic and xenobiotic control of thyroid hormone metabolism

目前的建议侧重于这样一个概念，即甲状腺激素激活(T4到T3转换)通过 2型脱碘酶(D2)在燃料动态平衡和能量消耗中起着关键作用。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。最近，人类骨骼肌中D2活性的发现产生了 相当令人兴奋，因为脱碘是新陈代谢的一种常见机制 在这种背景下，我们立即对BAT D2在一种 饮食诱导肥胖抵抗的小鼠模型。在这个模型中，补充0.5%的胆汁酸 防止动物在进食高脂肪食物时变得超重或胰岛素抵抗。激烈的 合作研究通过以下途径首次认识到FXR非依赖的代谢途径 哪些胆汁酸与G蛋白偶联受体TGR5相互作用，从而刺激代谢中的D2 相关组织包括蝙蝠和人骨骼肌细胞。我们的初步研究表明，其他； GPCRs也刺激D2。这些惊人的数据表明，控制D2的代谢物的光谱，以及 这种机制在其中起作用的靶组织的范围可能比以前更广泛 想着。考虑到这一点，我们已经开始寻找新的D2调节物质，并已经 初步证据支持对异类化合物有显著的调控作用。了解如何 来自快速波动的内源分子和外源因子的代谢信号通过 D2通路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，我们希望确定新的靶点和方法 代谢紊乱的治疗干预，包括II型糖尿病、肥胖和代谢紊乱 综合症。

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.