Endocrine Abstracts

A normal thyroid status is crucial for correct tissue and organ function, including temperature homeostasis. The tissue-specific actions of thyroid hormone on body temperature regulation in humans and rodents are largely modulated via the nuclear thyroid hormone receptor TRα1. Consequently, mice expressing a mutant TRα1R384C display a reduced core body temperature at 22°C caused by excessive heat loss via the tail. Surprisingly, the hypothermic phenotype of TRα1 mutant mice cannot be rescued by housing the mice at 30°C which negates tail heat loss. The observed lack of a compensatory brown fat activation suggests that the central regulation of temperature homeostasis may be impaired in TRα1-mutant mice. Ultimately, we hypothesize that TRα1-mutant mice have a lower central body temperature set-point due to yet unknown actions of the mutant TRα1 in the brain. To test whether a mutant TRα1 in the brain contributes to a lower body temperature phenotype, we injected adeno-associated viral vectors carrying the dominant-negative TRα1R384C into the hypothalamus, targeting the POA an area known to be involved in whole-body thermoregulation. Interestingly, preliminary data suggests that the expression of dominant-negative TRα1 in the hypothalamus indeed lowers body temperature independent of caloric intake. Further experiments aim at dissecting the contributions of dominant-negative TRα1 in the brain on resting metabolic rate and other metabolic parameters.