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 α1 (TRα1) and thyroid hormone receptor beta (TRß), 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 TRα1 (TRα1+m) as well as TRß 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 TRα1 on body temperature after adeno-associated virus (AAV)-mediated expression in the hypothalamus, a region known to be involved in thermoregulation. Results: While TRß seems to play a negligible role in body temperature regulation, TRα1+m mice had lower body temperature, which was surprisingly not entirely normalized at 30°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 TRα1+m mice, suggesting that the mutant TRα1 confers an altered central temperature set point in these mice. When we tested this hypothesis more directly by expressing the dominant-negative TRα1 selectively in the hypothalamus via AAV transfection, we observed a similarly reduced body temperature at room temperature and 30°C. Conclusion: Our data suggest that TRα1 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.

Resistance to thyroid hormone induced tachycardia in RTHα syndrome.

Mutations in thyroid hormone receptor α1 (TRα1) cause Resistance to Thyroid Hormone α (RTHα), a disorder characterized by hypothyroidism in TRα1-expressing tissues including the heart. Surprisingly, we report that treatment of RTHα patients with thyroxine to overcome tissue hormone resistance does not elevate their heart rate. Cardiac telemetry in male, TRα1 mutant, mice indicates that such persistent bradycardia is caused by an intrinsic cardiac defect and not due to altered autonomic control. Transcriptomic analyses show preserved, thyroid hormone (T3)-dependent upregulation of pacemaker channels (Hcn2, Hcn4), but irreversibly reduced expression of several ion channel genes controlling heart rate. Exposure of TRα1 mutant male mice to higher maternal T3 concentrations in utero, restores altered expression and DNA methylation of ion channels, including Ryr2. Our findings indicate that target genes other than Hcn2 and Hcn4 mediate T3-induced tachycardia and suggest that treatment of RTHα patients with thyroxine in high dosage without concomitant tachycardia, is possible.

Small extracellular vesicle-mediated targeting of hypothalamic AMPKα1 corrects obesity through BAT activation.

Current pharmacological therapies for treating obesity are of limited efficacy. Genetic ablation or loss of function of AMP-activated protein kinase alpha 1 (AMPKα1) in steroidogenic factor 1 (SF1) neurons of the ventromedial nucleus of the hypothalamus (VMH) induces feeding-independent resistance to obesity due to sympathetic activation of brown adipose tissue (BAT) thermogenesis. Here, we show that body weight of obese mice can be reduced by intravenous injection of small extracellular vesicles (sEVs) delivering a plasmid encoding an AMPKα1 dominant negative mutant (AMPKα1-DN) targeted to VMH-SF1 neurons. The beneficial effect of SF1-AMPKα1-DN-loaded sEVs is feeding-independent and involves sympathetic nerve activation and increased UCP1-dependent thermogenesis in BAT. Our results underscore the potential of sEVs to specifically target AMPK in hypothalamic neurons and introduce a broader strategy to manipulate body weight and reduce obesity.

3-Iodothyronamine Induces Tail Vasodilation Through Central Action in Male Mice.

3-Iodothyronamine (3-T1AM) is an endogenous thyroid hormone (TH)-derived metabolite that induces severe hypothermia in mice after systemic administration; however, the underlying mechanisms have remained enigmatic. We show here that the rapid 3-T1AM-induced loss in body temperature is a consequence of peripheral vasodilation and subsequent heat loss (e.g., over the tail surface). The condition is subsequently intensified by hypomotility and a lack of brown adipose tissue activation. Although the possible 3-T1AM targets trace amine-associated receptor 1 or α2a-adrenergic receptor were detected in tail artery and aorta respectively, myograph studies did not show any direct effect of 3-T1AM on vasodilation, suggesting that its actions are likely indirect. Intracerebroventricular application of 3-T1AM, however, replicated the phenotype of tail vasodilation and body temperature decline and led to neuronal activation in the hypothalamus, suggesting that the metabolite causes tail vasodilation through a hypothalamic signaling pathway. Consequently, the 3-T1AM response constitutes anapyrexia rather than hypothermia and closely resembles the heat-stress response mediated by hypothalamic temperature-sensitive neurons. Our results thus underline the well-known role of the hypothalamus as the body's thermostat and suggest an additional molecular link between TH signaling and the central control of body temperature.