Cellular thyroid hormone signalling mechanisms during weight maintenance

甲状腺激素及其代谢产物(THM)是能量消耗(EE)和代谢的关键调节因子。体重变化和肥胖在一定程度上改变了循环中的THM，导致下丘脑-垂体-甲状腺(HPT)轴的适应及其反馈调节。THM的细胞内代谢和作用既受到循环THM变化的影响，也受到到达EE相关靶细胞和组织的营养、神经、免疫和内分泌信号的改变的影响。在第一个资助期，我们建立了Z项目患者血液中代谢相关蛋白质激素和THM的灵敏分析，以及进行维持体重循环方案的小鼠的血液和组织中的代谢相关蛋白激素和THM的敏感分析。由于血清THM只显示了轻微的变化，我们现在将检验这样的假设，即高水平的EE调节THM(例如，3，5T2和3T1AM)，由脱碘酶(D)活性局部产生的细胞内高水平的THM，通过细胞内THM信号机制促进和适应代谢反应。这些可能主要受循环血清THM以外的其他因素的调节。由于miR-146已知可以拮抗trβ的信号转导，tHM参与调节脂代谢、棕色脂肪组织(BAT)产热和HPT反馈调节的异构体，我们将在体内和体外探索miR-146是否通过减少细胞内THM信号级联来干扰能量代谢。这些以及细胞内丰富的3，5T2的作用靶点将在细胞模型中进行分析。将开发组织衍生激素3，5T2和虹膜蛋白的免疫学检测方法。我们将继续为Z-Study和其他CRG项目贡献我们在多重和LC-MS/MS激素测量方面的专业知识。我们的项目将深入了解细胞内丰富的THM的作用机制，这可能被证明是有用的诊断工具和/或治疗策略，以保持体重。

Thyroid hormone and their metabolites (THM) are key regulators of energy expenditure (EE) and metabolism. Weight changes and obesity alter circulating THM to some extent and lead to adaptations of the hypothalamus-pituitary-thyroid (HPT) axis and its feedback regulation. Intracellular metabolism and action of THM is affected both by changes of circulating THM and by altered nutritional, neuronal, immunological and endocrine signals reaching target cells and tissues relevant to EE. During the first funding period we established sensitive assays of metabolically relevant protein hormones and THM in the blood of Z-project patients as well as in the blood and tissues of mice undergoing the MAINTAIN weight cycling protocol. As serum THM showed only modest changes we will now test the hypothesis that high intracellular levels of EE-regulating THM (e.g. 3,5T2 and 3T1AM), locally generated by deiodinase (D) activities contribute to and adapt to the metabolic response by intracrine THM signalling mechanisms. These might be regulated primarily by other factors than circulating serum THM. As miR-146 is known to antagonize signalling of TRβ, the isoform involved in THM regulated lipid metabolism, brown adipose tissue (BAT) thermogenesis and HPT feedback regulation, we will explore in vivo and in vitro whether miR146 interferes with energy metabolism by reducing intracrine THM signalling cascades. These as well as targets for action of the intracellularly abundant 3,5T2 will be analyzed in cellular models. Immunological detection methods will be developed for tissue-derived hormones 3,5T2 and irisin. We will continue to contribute our expertise in multiplex and LC-MS/MS hormone measurements for the Z-study and other CRG projects. Our project will provide insight into mechanisms of action of intracellular abundant THM, which might prove useful as diagnostic tools and/or therapeutic strategies for weight maintenance.