Hypermetabolism in mice caused by the central action of an unliganded thyroid hormone receptor α1

Abstract

Thyroid hormone, via its nuclear receptors TRalpha and TRbeta, controls metabolism by acting locally in peripheral tissues and centrally by regulating sympathetic signaling. We have defined aporeceptor regulation of metabolism by using mice heterozygous for a mutant TRalpha1 with low affinity to T3. The animals were hypermetabolic, showing strongly reduced fat depots, hyperphagia and resistance to diet-induced obesity accompanied by induction of genes involved in glucose handling and fatty acid metabolism in liver and adipose tissues. Increased lipid mobilization and beta-oxidation occurred in adipose tissues, whereas blockade of sympathetic signaling to brown adipose tissue normalized the metabolic phenotype despite a continued perturbed hormone signaling in this cell type. The results define a novel and important role for the TRalpha1 aporeceptor in governing metabolic homeostasis. Furthermore, the data demonstrate that a nuclear hormone receptor affecting sympathetic signaling can override its autonomous effects in peripheral tissues.

Thyroid hormone modulates glucose production via a sympathetic pathway from the hypothalamic paraventricular nucleus to the liver

“…Recent studies in mice have shown that suppression of TR␣1 signaling via a mutation causing a 10-fold lower affinity for T 3 enhances basal metabolism. This appeared to be mediated via increased sympathetic tone to brown adipose tissue, overriding the peripheral actions of the receptor (25). These observations suggested an important role for TR␣1 in regulating sympathetic outflow from the hypothalamus.…”

Thyroid hormone is required for hypothalamic neurons regulating cardiovascular functions

“…Mice heterozygous for a point mutation in TRα1 represent an established animal model for receptor-mediated hypothyroidism (9,11). Their adult phenotype is a combination of irreversible defects caused by the defective TRα1 signaling during brain development and impairments in acute TRα1 signaling (10,12). However, as the acute impairments in TRα1 signaling can be reversed by treating the Thra1 +/m mice with T3 (11), the identification of irreversible developmental defects becomes possible.…”

“…An additional melting curve was recorded to confirm the specificity of the reaction. The primer sequences have been published previously (10) or are listed in Supplemental Table 1.…”

“…Conversely, hypothyroid patients often suffer from weight gain and bradycardia (3). While most of the cardiovascular and metabolic effects of thyroid hormone have been attributed to direct actions in the corresponding peripheral tissues, such as heart (4) or skeletal muscle and fat (5,6), recent studies have demonstrated that the hormone modulates these processes also through the brain (7): injections of thyroid hormone into different brain regions stimulate energy expenditure (8), and thyroid hormone signaling is required to establish the metabolic set point during embryonal development (9,10).…”

Thyroid hormone action in metabolic regulation

“…These observations suggest that TRα1PV dysregulates PPARγ expression which results in impaired adipogenesis of WAT in TRα1 PV/N mice. Similar to TRα1 PV/N mice, the TRα1R384C knock-in mice exhibit a lean phenotype with reduction in white fat mass and decreased leptin levels (Sjögren et al, 2007). TRα1R384C mice are hypermetabolic and resistant to diet-induced obesity.…”