Non Classical Concepts of Thyroid Hormone Action in the Regulation of Body Temperature

甲状腺激素是典型的外周生热调节因子。然而，最近的研究表明，它在大脑和心血管系统中的作用也与体温的调节有很大的关系。此外，已经确定了甲状腺激素的特定下游代谢物，这些代谢物似乎在温度调节中也有很强的作用。该项目现在旨在测试这样一种假设，即甲状腺激素及其代谢物3-碘甲状腺原胺和3,5-二碘甲状腺原氨酸的热调节作用实际上可能由中枢或心血管活动介导，例如通过调节散热。我们将使用体内和离体研究的独特组合来解剖代谢物的中枢和外周作用，包括立体定向脑注射，钢丝肌图测试血管反应，以及无线遥测来监测有意识和自由活动的动物的体温和心率。此外，我们将使用我们已经建立的红外热像仪来量化整个动物的热量产生和散热。为了揭示潜在的分子机制，基因表达研究将使用微阵列、qPCR和原位杂交/免疫组织化学技术进行。该结果将为甲状腺激素及其代谢物如何调节体温，以及它们如何影响不同体温调节系统之间的相互作用提供新颖而全面的见解。因此，该项目挑战了甲状腺激素在生热作用中的经典概念，旨在揭示甲状腺激素在体温调节中的新颖、非经典机制。

Thyroid hormone is a classical regulator of peripheral thermogenesis. Recent studies however suggest that its actions in brain and the cardiovascular system are also of great relevance for the regulation of body temperature. Moreover, specific downstream metabolites of thyroid hormone have been identified, which also seem to have strong effects in temperature regulation.The proposed project now aims to test the hypothesis that the thermoregulatory effects of thyroid hormone and its metabolites 3-iodothyronamine and 3,5-diiodothyronine could in fact be mediated by central or cardiovascular actions, for instance by modulating heat dissipation. We will use a unique combination of in vivo and ex vivo studies to dissect the central and peripheral actions of the metabolites, including stereotaxic brain injections, wire myography to test vascular responses, and radiotelemetry to monitor body temperature and heart rate in the conscious and freely moving animal. Moreover, we will employ our established infrared thermography to quantify heat generation and heat dissipation in the whole animal. To unravel the underlying molecular mechanisms, gene expression studies will be conducted using microarray, qPCR and in situ hybridization / immunohistochemistry techniques.The results will provide novel and holistic insight into how thyroid hormone and its metabolites regulate body temperature, and how they affect the interplay between the different thermoregulatory systems. The proposed project therefore challenges the classical concepts of thyroid hormone in thermogenesis, and aims to unravel novel, non-classical mechansims of thyroid hormone action in the regulation of body temperature.