Cellular thyroid hormone signalling mechanisms during weight maintenance

体重维持过程中细胞甲状腺激素信号传导机制

• 批准号: 225913302
• 负责人: Professor Dr. Josef Köhrle
• 金额: --
• 依托单位: Institut für Biochemie und Molekularbiologie (IBMB)
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/225913302?language=en
• 关键词: Cellular; thyroid; hormone; signalling; mechanisms

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.

甲状腺激素及其代谢物（THM）是能量消耗（EE）和新陈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THM，并导致下丘脑-垂体-甲状腺（HPT）轴及其反馈调节的适应。 THM 的细胞内代谢和作用受到循环 THM 变化以及到达与 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。在第一个资助期间，我们对 Z 项目患者的血液以及接受维持体重循环方案的小鼠的血液和组织中代谢相关的蛋白质激素和 THM 进行了灵敏的检测。由于血清 THM 仅显示出适度的变化，我们现在将测试以下假设：由脱碘酶 (D) 活性局部产生的高细胞内水平的 EE 调节 THM（例如 3,5T2 和 3T1AM）有助于并适应内分泌 THM 信号机制的代谢反应。这些可能主要受到循环血清 THM 以外的其他因素的调节。由于已知 miR-146 可以拮抗 TRβ 信号传导，TRβ 是参与 THM 调节脂质代谢、棕色脂肪组织 (BAT) 产热和 HPT 反馈调节的亚型，因此我们将在体内和体外探索 miR146 是否通过减少分泌内 THM 信号级联反应来干扰能量代谢。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。将开发组织源激素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，这可能被证明可用作维持体重的诊断工具和/或治疗策略。