Cellular thyroid hormone signalling mechanisms during weight maintenance

甲状腺激素及其代谢物（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循环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循环THM的变化影响，也受到达与EE相关的靶细胞和组织的营养、神经元、免疫和内分泌信号改变的影响。在第一个资助期内，我们建立了Z-project患者血液以及维持体重循环方案小鼠血液和组织中代谢相关蛋白激素和THM的敏感检测方法。由于血清THM仅显示出适度的变化，我们现在将验证高水平的细胞内e调节THM（例如3,5t2和3T1AM）的假设，该假设是由脱碘酶(D)活性局部产生的，有助于并适应分泌内THM信号传导机制的代谢反应。这些可能主要受循环血清THM以外的其他因素调节。由于已知miR-146可以拮抗TRβ信号传导，THM参与的亚型调节脂质代谢、棕色脂肪组织（BAT）产热和HPT反馈调节，我们将在体内和体外探索miR146是否通过减少分泌内THM信号级联来干扰能量代谢。这些以及细胞内丰富的3,5t2的作用靶标将在细胞模型中进行分析。开发组织源性激素3、5T2和鸢尾素的免疫学检测方法。我们将继续为z研究和其他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/或体重维持的治疗策略。

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.