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

甲状腺激素在体温调节中的重要作用是众所周知的，从甲状腺功能亢进患者的热敏性可以看出。最近，我们能够在小鼠模型中证明，激素通过引起肌肉的高热来增加体温，与发烧/发热时体温设定点的中心升高平行。然而，甲状腺激素协调产热反应的精确神经解剖学基础仍然是个谜。在这个提议中，我们的目标是在大脑中确定甲状腺激素作用的新位点，这可能介导其对体温调节的影响。利用几种不同的甲状腺激素信号改变的动物模型，结合PET/CT或红外热成像等尖端技术，我们将描述体温调节的协调变化，特别关注棕色脂肪产热。因此，我们的目的是剖析与大脑活动相关的外周热疗和中枢热疗之间的串扰。我们的初步研究已经确定了几个被甲状腺激素激活的大脑区域，我们认为这些区域参与了体温调节。我们将使用甲状腺激素的立体定向输送到大脑中来测试这一假设，并旨在通过生化分类和激活神经元的分析来确定精确的神经元群。我们提出的项目将更好地了解甲状腺激素如何控制体温和随后的能量消耗，这对代谢紊乱（如肥胖或II型糖尿病）具有特别的转化相关性。

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.