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

甲状腺激素是外周产热的经典调节剂。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调节密切相关。此外，还发现了甲状腺激素的特定下游代谢物，它们似乎也有很强的温度调节作用。拟议的项目现在旨在验证一种假设，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体温调节作用实际上可能是通过中枢或心血管作用来调节的，例如通过调节散热。我们将使用一种独特的体内和体外研究相结合的方法来剖析代谢物的中枢和外周作用，包括立体定向脑注射、线状肌肉造影术来测试血管反应，以及无线电遥测来监测清醒和自由活动的动物的体温和心率。此外，我们将使用我们建立的红外热像仪来量化整个动物的热量产生和热量消耗。为了揭示其潜在的分子机制，将利用基因芯片、定量聚合酶链式反应和原位杂交/免疫组织化学技术进行基因表达研究。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的、全面的见解。因此，这项拟议的项目挑战了甲状腺激素在产热中的经典概念，并旨在揭开甲状腺激素在体温调节中作用的新的、非经典的机制。

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.