NeurObesity Group, Department of Physiology, CiMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria & CIBER de la Fisiología de la Obesidad y la Nutrición (CIBEROBN), Santiago de Compostela 15782, Spain.
Univ Lyon, ENS de Lyon, INRAE, CNRS, Institut de Génomique Fonctionnelle de Lyon, Lyon 69364, France.
Endocrinology. 2023 Feb 11;164(4). doi: 10.1210/endocr/bqad034.
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.
甲状腺激素增加能量消耗。它的作用是通过 TR 介导的，TR 是存在于外周组织和中枢神经系统（特别是在下丘脑神经元）中的核受体。在这里，我们研究了甲状腺激素信号在神经元中的重要性，特别是对能量消耗的调节。我们使用 Cre/LoxP 系统生成了神经元中缺乏功能性 TR 的小鼠。在代谢调节的中心——下丘脑，突变存在于 20%到 42%的神经元中。表型分析是在触发适应性产热的生理条件下进行的：寒冷和高脂肪饮食（HFD）喂养。突变小鼠在棕色和腹股沟白色脂肪组织中的产热潜能受损，更容易发生饮食诱导的肥胖。它们在正常饮食下的能量消耗减少，在 HFD 上的体重增加更多。这种对肥胖的更高敏感性在体温适中时消失了。同时，与对照组相比，突变体中 AMPK 通路在腹内侧下丘脑被激活。一致地，通过酪氨酸羟化酶表达来可视化的交感神经系统（SNS）输出在突变体的棕色脂肪组织中较低。相比之下，突变体中缺乏 TR 信号并不影响它们对寒冷暴露的反应能力。这项研究提供了第一个遗传证据，表明甲状腺激素信号在神经元中发挥重要作用，以刺激某些适应性产热的生理背景下的能量消耗。TR 在神经元中的功能是限制对 HFD 的体重增加，而这种作用与 SNS 输出的增强有关。
