The Hypothalamic Paraventricular Nucleus Is the Center of the Hypothalamic?Pituitary?Thyroid Axis for Regulating Thyroid Hormone Levels
The Hypothalamic Paraventricular Nucleus Is the Center of the Hypothalamic?Pituitary?Thyroid Axis for Regulating Thyroid Hormone Levels
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下丘脑室旁核是下丘脑、垂体、甲状腺轴调节甲状腺激素水平的中心
DOI：
10.1089/thy.2021.0444
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发表时间：
2021
期刊：
影响因子：
6.6
通讯作者：
Yamada Masanobu
中科院分区：
文献类型：
--
作者：
Kondo Yuri;Ozawa Atsushi;Kohno Daisuke;Saito Kazuma;Buyandalai Battsetseg;Yamada Sayaka;Horiguchi Kazuhiko;Nakajima Yasuyo;Shibusawa Nobuyuki;Harada Akihiro;Yokoo Hideaki;Akiyama Hideo;Sasaki Tsutomu;Kitamura Tadahiro;Yamada Masanobu
背景：促甲状腺激素释放激素（TRH）是第一个分离到的刺激垂体促甲状腺激素（TSH）分泌的下丘脑激素。TRH后来也被发现是垂体催乳素的刺激物，并分布在整个大脑，胃肠道和胰腺β细胞中。我们先前报道了TRH基因敲除小鼠（传统TRHKO）的发展，由于胰岛素分泌不足，其表现出特征性的三级甲状腺功能减退和葡萄糖耐量受损。虽然在过去的50年里，许多研究者，包括我们，试图确定下丘脑核负责下丘脑-垂体-甲状腺（HPT）轴，它仍然模糊，因为广泛表达的TRH.Methods：为了确定下丘脑区域功能负责HPT轴，我们建立了室旁核（PVN）特异性TRH基因敲除（PVN-TRHKO）小鼠matingTrhfloxed小鼠和一心同源1（Sim 1）-Cre转基因小鼠。我们最初证实，大多数Sim 1的表达在PVN使用Sim 1-Cre/tdTomato mice.Results：这些PVN-TRHKO小鼠表现出三级甲状腺功能减退症类似于传统的TRHKO小鼠，但是，他们没有表现出糖耐量受损观察到后者，这表明TRH从非PVN来源是必不可少的葡萄糖调节。此外，催乳素的表达严重减少，观察到在PVN-TRHKO小鼠的垂体相比，在TRHKO mice.Conclusions：这些研究结果是确凿的证据表明，PVN是HPT轴的中心，用于调节血清甲状腺激素水平和血清TSH水平不降低在三级甲状腺功能减退症。我们还注意到来自PVN的TRH调节催乳素，而来自非PVN来源的TRH调节葡萄糖代谢。
Background:Thyrotropin-releasing hormone (TRH) was the first hypothalamic hormone isolated that stimulates pituitary thyrotropin (TSH) secretion. TRH was also later found to be a stimulator of pituitary prolactin and distributed throughout the brain, gastrointestinal tract, and pancreatic β cells. We previously reported the development of TRH null mice (conventional TRHKO), which exhibit characteristic tertiary hypothyroidism and impaired glucose tolerance due to insufficient insulin secretion. Although in the past five decades many investigators, us included, have attempted to determine the hypothalamic nucleus responsible for the hypothalamic–pituitary–thyroid (HPT) axis, it remained obscure because of the broad expression of TRH.Methods:To determine the hypothalamic region functionally responsible for the HPT axis, we established paraventricular nucleus (PVN)-specific TRH knockout (PVN-TRHKO) mice by matingTrhfloxed mice and single-minded homolog 1 (Sim1)-Cre transgenic mice. We originally confirmed that most Sim1 was expressed in the PVN using Sim1-Cre/tdTomato mice.Results:These PVN-TRHKO mice exhibited tertiary hypothyroidism similar to conventional TRHKO mice; however, they did not show the impaired glucose tolerance observed in the latter, suggesting that TRH from non-PVN sources is essential for glucose regulation. In addition, a severe reduction in prolactin expression was observed in the pituitary of PVN-TRHKO mice compared with that in TRHKO mice.Conclusions:These findings are conclusive evidence that the PVN is the center of the HPT axis for regulation of serum levels of thyroid hormones and that the serum TSH levels are not decreased in tertiary hypothyroidism. We also noted that TRH from the PVN regulated prolactin, whereas TRH from non-PVN sources regulated glucose metabolism.