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

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.