Maintenance of the thyroid axis during diet-induced obesity in rodents is controlled at the central level.
Maintenance of the thyroid axis during diet-induced obesity in rodents is controlled at the central level.
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DOI：
10.1152/ajpendo.00448.2010
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发表时间：
2010-09
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影响因子：
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通讯作者：
M. Perelló;I. Çakır;Nicole E. Cyr;A. Romero;R. Stuart;Franck Chiappini;A. Hollenberg;E. Nillni
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文献类型：
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作者：
M. Perelló;I. Çakır;Nicole E. Cyr;A. Romero;R. Stuart;Franck Chiappini;A. Hollenberg;E. Nillni
下丘脑-垂体-甲状腺（HPT）轴是维持能量消耗和体重的主要贡献者，脂肪细胞激素瘦素通过增加进食状态下TRH水平来调节该轴。瘦素直接刺激下丘脑室旁核（PVN;直接途径）中的TRH，并通过调节下丘脑弓状核（ARC;间接途径）中的阿黑皮素原神经元间接刺激TRH。间接途径在瘦动物中是完全功能性的，而在饮食诱导的肥胖症（DIO）期间由于瘦素抵抗的建立而不活跃。尽管如此，肥胖人类和啮齿类动物的HPT轴活性仍保持在正常水平或略高。因此，在这项研究中，我们的目的是确定机制（S）的HPT轴仍然活跃，尽管瘦素抵抗。结合使用Sprague-Dawley大鼠生理模型和在瘦素受体中具有突变的Zuker大鼠，我们能够证明在DIO条件下，HPT轴在中枢水平受到调节，但仅通过瘦素作用于TRH神经元的直接途径。脱碘酶存在于许多组织中，负责转化甲状腺激素，在瘦和DIO动物之间没有统计学差异。这些数据表明，在肥胖动物中观察到的T（4/3）增加主要是由于中枢瘦素作用。我们还发现，T（3）对前TRH原基因的反馈抑制部分由瘦素诱导的pSTAT 3信号转导通过TRH启动子控制。T（3）和pSTAT 3信号之间的这种相互作用关系似乎对在肥胖等疾病中维持HPT轴在正常水平至关重要。
The hypothalamic-pituitary-thyroid (HPT) axis is a major contributor in maintaining energy expenditure and body weight, and the adipocyte hormone leptin regulates this axis by increasing TRH levels in the fed state. Leptin stimulates TRH directly in the hypothalamic paraventricular nucleus (PVN; direct pathway) and indirectly by regulating proopiomelnocortin neurons in the hypothalamic arcuate nucleus (ARC; indirect pathway). Whereas the indirect pathway is fully functional in lean animals, it is inactive during diet-induced obesity (DIO) because of the establishment of leptin resistance. Despite this, the HPT axis activity in obese humans and rodents remains within the normal levels or slightly higher. Therefore, in this study, we aimed to determine the mechanism(s) by which the HPT axis is still active despite leptin resistance. With a combination of using the Sprague-Dawley rat physiological model and the Zuker rat that bears a mutation in the leptin receptor, we were able to demonstrate that under DIO conditions the HPT axis is regulated at the central level, but only through the direct pathway of leptin action on TRH neurons. Deiodinase enzymes, which are present in many tissues and responsible for converting thyroid hormones, were not statistically different between lean and DIO animals. These data suggest that the increase in T(4/3) seen in obese animals is due mostly to central leptin action. We also found that T(3) feedback inhibition on the prepro-TRH gene is controlled partially by leptin-induced pSTAT3 signaling via the TRH promoter. This interactive relationship between T(3) and pSTAT3 signaling appears essential to maintain the HPT axis at normal levels in conditions such as obesity.