Hypothalamic Thyroid Hormone Receptor α1 Signaling Controls Body Temperature

Background: The importance of thyroid hormones (THs) for peripheral body temperature regulation has been long recognized, as medical conditions such as hyper- and hypothyroidism lead to alterations in body temperature and energy metabolism. In the past decade, the brain actions of THs and their respective nuclear receptors, thyroid hormone receptor alpha 1 (TR alpha 1) and thyroid hormone receptor beta (TR beta), coordinating body temperature regulation have moved into focus. However, the exact roles of the individual TR isoforms and their precise neuroanatomical substrates remain poorly understood.Methods: Here we used mice expressing a mutant TR alpha 1 (TR alpha 1+m) as well as TR beta knockouts to study body temperature regulation using radiotelemetry in conscious and freely moving animals at different ambient temperatures, including their response to oral 3,3 ',5-triiodothyronine (T3) treatment. Subsequently, we tested the effects of a dominant-negative TR alpha 1 on body temperature after adeno-associated virus (AAV)-mediated expression in the hypothalamus, a region known to be involved in thermoregulation.Results: While TR beta seems to play a negligible role in body temperature regulation, TR alpha 1+m mice had lower body temperature, which was surprisingly not entirely normalized at 30 degrees C, where defects in facultative thermogenesis or tail heat loss are eliminated as confounding factors. Only oral T3 treatment fully normalized the body temperature profile of TR alpha 1+m mice, suggesting that the mutant TR alpha 1 confers an altered central temperature set point in these mice. When we tested this hypothesis more directly by expressing the dominant-negative TR alpha 1 selectively in the hypothalamus via AAV transfection, we observed a similarly reduced body temperature at room temperature and 30 degrees C.Conclusion: Our data suggest that TR alpha 1 signaling in the hypothalamus is important for maintaining body temperature. However, further studies are needed to dissect the precise neuroanatomical substrates and the downstream pathways mediating this effect.