부산대학교 도서관

Thyroid hormone increases energy expenditure. Its action is mediated by TR, nuclear receptors present in peripheral tissues and in the central nervous system, particularly in hypothalamic neurons. Here, we address the importance of thyroid hormone signaling in neurons, in general for the regulation of energy expenditure. We generated mice devoid of functional TR in neurons using the Cre/LoxP system. In hypothalamus, which is the center for metabolic regulation, mutations were present in 20% to 42% of the neurons. Phenotyping was performed under physiological conditions that trigger adaptive thermogenesis: cold and high-fat diet (HFD) feeding. Mutant mice displayed impaired thermogenic potential in brown and inguinal white adipose tissues and were more prone to diet-induced obesity. They showed a decreased energy expenditure on chow diet and gained more weight on HFD. This higher sensitivity to obesity disappeared at thermoneutrality. Concomitantly, the AMPK pathway was activated in the ventromedial hypothalamus of the mutants as compared with the controls. In agreement, sympathetic nervous system (SNS) output, visualized by tyrosine hydroxylase expression, was lower in the brown adipose tissue of the mutants. In contrast, absence of TR signaling in the mutants did not affect their ability to respond to cold exposure. This study provides the first genetic evidence that thyroid hormone signaling exerts a significant influence in neurons to stimulate energy expenditure in some physiological context of adaptive thermogenesis. TR function in neurons to limit weight gain in response to HFD and this effect is associated with a potentiation of SNS output. Key Words: thyroid hormone, adaptive thermogenesis, cold exposure, diet-induced obesity, neurons, brown adipose tissue, sympathetic nervous system (SNS) Abbreviations: AMPK, AMP-activated protein kinase; BAT, brown adipose tissue; CTRL, control mice; D2, type 2 deiodinase; DIO, diet-induced obesity; EE, energy expenditure; HFD, high-fat diet; ICV, intracerebroventricular; iWAT, inguinal WAT; LA, locomotive activity; NE, norepinephrine; NTRKO, mutant mice (Cre[3.sup.Tg/+][xThra.sup.AMI/+][Thrb.sup.lox/lox]); PTU, propylthiouracil; ROI, region of interest; RT-qPCR, quantitative reverse transcription--polymerase chain reaction; SNS, sympathetic nervous system; T3, triiodothyronine; T4, thyroxine; TH, thyroid hormones; UCP1, uncoupling protein 1; VMH, ventromedial hypothalamus; WAT, white adipose tissue; WT, wild-type.
As obesity and associated metabolic disorders became pandemic (1), the metabolic activities of thyroid hormone (3,3',5-triiodo-L-thyronine, or T3), the active metabolite of thyroxine (T4) gained renewed interest. Indeed, in humans, [...]