Diabetes：郭非凡等揭示外周ATF4调控肝脏胰岛感性的新功能

近日，国际文摘Diabetes应用软件发表了之副所长天津生科院营养生物科学深入研究之中心郭非凡组的深入研究论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该深入研究阐明了下丘脑酪氨酸核苷酸因子4 (ATF4) 通过诱导核糖体S6K腺苷(p70 S6K1)，进而抑制则有肝脏的人体内感持续性的分子机制，概述了下丘脑ATF4抑制则有代谢稳态的新功用。

2型号乳癌是一种慢持续性代谢持续性结核病，随着生活水平的日益增加，我国2型号乳癌的发病率急速增加。以外关于2型号乳癌的深入研究主要临近在肝脏等单个器官，而各个器官的交互起到对2型号乳癌受到影响的深入研究很少。周围神经，更是是下丘脑，在EVA则有民间组织的人体内感持续性抑制之中起非常不可忽视的起到，近年来已逐渐成为一个深入研究旅游者。ATF4是CREB家族之中的一个不可忽视成员，之后关于ATF4依赖性代谢的功用深入研究主要临近在则有民间组织，例如ATF4 下半身敲除小鼠会贫血，三酸甘油酯减少，能量消耗增加，人体内感持续性升高；成骨细胞之中特异持续性敲除ATF4也会增加人体内感持续性等。但是周围神经之中ATF4是否参与则有人体内感持续性的抑制尚属新闻报道。

郭非凡深入研究组的高级工程师张倩等人发现，通过第三脑室施打腺病毒介导的ATF4过理解能够引起肝脏的生长激素抗击，而显持续性特异性ATF4（dominant negative-ATF4）能够增加肝脏人体内感持续性；全面性深入研究表明ATF4对则有糖代谢的抑制是通过下丘脑S6K1以及肝脏迷走神经信号传播的；另外，本深入研究还表明了ATF4是之中枢细胞内诱导引起则有生长激素抗击更全面性之中的关键依赖性因子。

本深入研究概述了之中枢下丘脑ATF4在糖代谢之外的新功用，为深入研究之中枢抑制则有人体内感持续性提供了一个更全面性前景，并加宽了之中枢细胞内诱导对肝脏生长激素抗击的深入研究，丰富了人们对各个器官的交互起到依赖性糖代谢的认识，最大限度激化人们对乳癌及相关的代谢持续性结核病牵涉到机制的忽略。

该项工作得到国家自然生物科学基金、经济部以及之副所长等科研基金的支持。

与下丘脑相关的拓展学习者：

doi:10.2337/db12-1050PMC:PMID:

Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve

Qian Zhang, Junjie Yu, Bin Liu, Ziquan Lv, Tingting Xia, Fei Xiao, Shanghai Chen and Feifan Guo*

Recent studies he revealed that the central nervous system (CNS), particularly the hypothalamus, is critical for regulating insulin sensitivity in peripheral tissues. The aim of our current study is to investigate the possible involvement of hypothalamic Activating Transcription Factor (ATF) 4 in the regulation of insulin sensitivity in the liver. Here, we show that overexpression of ATF4 in the hypothalamus resulting from intrentricular (icv) injection of adenovirus expressing ATF4 induces hepatic insulin resistance in mice and that inhibition of hypothalamic ATF4 by icv adenovirus expressing a dominant-negative ATF4 variant has the opposite effect. We also show that hypothalamic ATF4-induced insulin resistance is significantly blocked by selective hepatic vagotomy or by inhibiting activity of the mammalian target of rapamycin (mTOR) downstream target S6K1. Finally, we show that inhibition of hypothalamic ATF4 reverses hepatic insulin resistance induced by acute brain endoplasmic reticulum (ER) stress. Taken together, our study describes a novel central pathway regulating hepatic insulin sensitivity that is mediated by hypothalamic ATF4/mTOR/S6K1 signaling and the vagus nerve, and demonstrate an important role for hypothalamic ATF4 in brain ER stress-induced hepatic insulin resistance. These results may lead to the identification of novel therapeutic targets for treating insulin resistance and associated metabolic diseases.