Novel Central Actions of Thyroid Hormone in the Control of Body Temperature

从甲亢患者的热敏感性来看，甲状腺激素在体温调节中的重要作用是众所周知的。最近，我们在一只小鼠模型中证明，这种激素通过在肌肉中引发体温升高，同时在发烧/发热时引起体温设定值的中心升高，从而提高体温。然而，甲状腺激素协调生热反应的精确神经解剖底物仍然是个谜。在这个建议中，我们的目标是确定甲状腺激素在大脑中的新作用部位，这些部位可能介导甲状腺激素对体温调节的影响。使用几种不同的甲状腺激素信号改变的动物模型，结合先进的技术，如PET/CT或红外热像仪，我们将描述体温调节的协调变化，特别是棕色脂肪的热生成。因此，我们的目标是剖析外周高热和中枢性高热之间的串扰与脑活动的相关性。我们的初步研究已经确定了几个由甲状腺激素激活的大脑区域，我们建议这些区域参与体温调节。我们将通过将甲状腺激素立体定向地输送到大脑中来验证这一假说，并旨在通过生化分类和激活神经元的特征来识别准确的神经元群体。我们提出的项目将提供更好的理解，了解甲状腺激素如何控制体温以及随后的能量消耗，这与肥胖或II型糖尿病等代谢疾病具有特别的翻译相关性。

Thyroid hormone is well known for its important role in body temperature regulation, as seen from the heat sensitivity of hyperthyroid patients. Recently, we were able to demonstrate in a mouse model that the hormone increases body temperature by eliciting hyperthermia in muscle in parallel with a central elevation of the body temperature set point as in fever/pyrexia. However, the precise neuroanatomical substrates by which thyroid hormone coordinates the thermogenic responses remain enigmatic.In this proposal we aim to identify novel sites of thyroid hormone action in the brain, which could mediate its effect on body temperature regulation. Using several different animal models with alterations in thyroid hormone signaling in combination with cutting edge technologies such as PET/CT or infrared thermography we will characterize the coordinated changes of thermoregulation with a special focus on brown fat thermogenesis. We thereby aim to dissect the crosstalk between the peripheral hyperthermia and the central pyrexia in correlation to brain activity. Our preliminary studies have already identified several brain regions that are activated by thyroid hormone, which we propose to be involved in body temperature regulation. We will test this hypothesis using stereotaxic delivery of thyroid hormone into the brain and aim to identify the precise neuronal populations using biochemical sorting and profiling of activated neurons.Our proposed project will provide a better understanding of how thyroid hormone controls body temperature and subsequently energy expenditure, which is of particular translational relevance for metabolic disorders such as obesity or type II diabetes.