Inappropriate heat dissipation ignites brown fat thermogenesis in mice with a mutant thyroid hormone receptor α1

Abstract

Thyroid hormone is a major regulator of thermogenesis, acting both in peripheral organs and on central autonomic pathways. Mice heterozygous for a point mutation in thyroid hormone receptor α1 display increased thermogenesis as a consequence of high sympathetic brown fat stimulation. Surprisingly, despite the hypermetabolism, their body temperature is not elevated. Here we show, using isolated tail arteries, that defective thyroid hormone receptor α1 signaling impairs acetylcholine-mediated vascular relaxation as well as phenylephrine-induced vasoconstriction. Using infrared thermography on conscious animals, we demonstrate that these defects severely interfere with appropriate peripheral heat conservation and dissipation, which in turn leads to compensatory alterations in brown fat activity. Consequently, when the vasoconstrictive defect in mice heterozygous for a point mutation in thyroid hormone receptor α1 was reversed with the selective α1-adrenergic agonist midodrine, the inappropriate heat loss over their tail surface was reduced, normalizing brown fat activity and energy expenditure. Our analyses demonstrate that thyroid hormone plays a key role in vascular heat conservation and dissipation processes, adding a unique aspect to its well-documented functions in thermoregulation. The data thus facilitate understanding of temperature hypersensitivity in patients with thyroid disorders. Moreover, the previously unrecognized connection between cardiovascular regulation and metabolic activity revealed in this study challenges the interpretation of several experimental paradigms and questions some of the currently derived hypotheses on the role of thyroid hormone in thermogenesis.adipose tissue | tail temperature T hyroid hormone affects energy metabolism, body temperature, and cardiovascular function (1, 2). This is evident in hypo-and hyperthyroid patients, who display metabolic and cardiovascular problems as well as inadequacies in heat and cold tolerance (3, 4). The latter effects are thought to be a consequence of a shift in obligatory thermogenesis, because thyroid hormone affects basal metabolic rate through the regulation of genes controlling cellular metabolism and mitochondrial function. In addition, facultative thermogenesis, brought about by shivering and brown adipose tissue (BAT) activation (5, 6), is also modulated by thyroid hormone. The recent discovery of BAT in adult humans, where previously thought to exist only in rodents and neonates (7), suggests that the role of BAT in thermoregulation and energy expenditure may be underestimated. Recently, a new role of thyroid hormone in facultative thermogenesis has emerged, controlling BAT via the central nervous system (8, 9). The importance of central thyroid hormone receptor α1 (TRα1) signaling for BAT activity was further supported by findings in mice heterozygous for a R384C mutation in TRα1 (TRα1+m), which display a strong hypermetabolism as the result of a central overactivation of BAT (10). However, the finding was unexpected, as the specific ...

Insufficient glucose supply is linked to hypothermia upon cold exposure in high-fat diet-fed mice lacking PEMT

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