New Targets of Thyroid Hormone Action

项目摘要 甲状腺激素(TH)是人体新陈代谢和体重的重要调节因子。的确， TH已被证明可以调节能量消耗、血脂水平和胰岛素敏感性 改善新陈代谢结果。由于这些有益的影响，TH或其类似物之一是 治疗多种代谢性疾病的潜在疗法。然而，如果过量服用 TH有明显的副作用，特别是对心脏和骨骼。值得注意的是，这一行动 人类几乎完全是由促甲状腺激素(TSH)测定确定的 仅取决于下丘脑和脑下垂体的活动。因此，有一个 迫切需要改进的生物标志物，以便对TH治疗进行量身定制以改进 新陈代谢健康，并允许增强安全性。为了开始实现这一点，我们使用了 代谢组学和小鼠遗传模型开始表征TH敏感性 活体内的通路。我们的初步工作已经确定了独特的代谢物，由 TH既可以作为生物标志物，也可以作为甲状腺激素作用的中介。在这 在第一个目标中，我们将通过以下方式扩展我们对代谢物谱调控的分析 以组织特异性和TH受体特异性的方式，并将我们的分析扩展到人类 这是第一次。在第二个目标中，我们将确定TH调节的机制 蛋氨酸代谢，可能是关键的能力，控制基因表达和 调节脂肪酸氧化等程序。在第三个目标中，我们将使用新的基因 确定TH如何控制胆固醇代谢的小鼠模型获得进一步的了解 转化为受TH调控的关键途径。总之，完成这些目标将提供一个新的 了解和定义体内作用的平台。

Project Summary Thyroid hormone (TH) is a critical regulator of metabolism and body weight in humans. Indeed, TH has been shown to regulate energy expenditure, lipid levels and insulin sensitivity to improve metabolic outcome. Because of these beneficial effects, TH or one of its analogs are potential therapeutics for a wide variety of metabolic disease. However, if excessively dosed TH has significant side effects especially on the heart and bone. Remarkably, TH action in humans is determined almost exclusively by the use of the thyrotropin (TSH) assay which depends only upon TH action at the level of the hypothalamus and pituitary. Thus, there is a critical need for improved biomarkers that would allow for tailoring of TH therapy to improve metabolic health and allow for enhanced safety. To begin to accomplish this we have used metabolomic profiling and mouse genetic models to began to characterize TH sensitive pathways in vivo. Our preliminary work has identified unique metabolites that are regulated by TH that serve both as biomarkers and also as mediators of thyroid hormone action. In this proposal in the first aim we will extend our analysis of the regulation of metabolite profiles by TH in a tissue-specific and TH receptor specific fashion and extend our analysis into humans for the first time. In the second Aim we will determine the mechanism by which TH regulates methionine metabolism which is likely critical to TH ability to control gene expression and regulate programs such as fatty acid oxidation. In the third Aim we will use novel genetic mouse models to determine how TH controls cholesterol metabolism gaining further insight into a key pathway regulated by TH. Together, completion of these Aims will provide for a new platform for both understanding and defining TH action in vivo.