Diabetes：郭非凡等揭示下丘脑ATF4诱导肝脏胰岛感性的新功能

近日，国际医学期刊Diabetes在线发表了当中科院天津生科院碳水化合物科学深入研究所郭非凡第三组的深入研究论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该深入研究阐明了神经系统活化转录因子4 (ATF4) 通过作用于核糖体S6K蛋白激酶(p70 S6K1)，进而抑止泌尿系统肝的胰脏高雅的分子会机制，概述了神经系统ATF4闭环泌尿系统代谢稳态的新系统。

2型乳癌是一种慢性代谢性疾病，随着生活水平的日益大幅提高，不能不2型乳癌的发病率急速增大。目前关于2型乳癌的深入研究主要集当中在肝等单个内脏，而各个内脏的交互依赖性对2型乳癌影响的深入研究很少。当实质上神经系统，更是是神经系统，在机体泌尿系统第三组织起来的胰脏高雅闭环当中起颇为重要的依赖性，近年来已随之被选为一个深入研究最近。ATF4是CREB的王室当中的一个重要成员，之前关于ATF4调控代谢的功能深入研究主要集当中在泌尿系统第三组织起来，例如ATF4 手脚敲除小鼠亦会心血管疾病，脂肪减少，利用效率增大，胰脏高雅升高；成骨细胞当中特异性敲除ATF4也亦会大幅提高胰脏高雅等。但是当实质上神经系统当中ATF4是否参与泌尿系统胰脏高雅的闭环尚无路透社。

郭非凡深入研究第三组的博士生张倩等人发现，通过第三脑室针头腺病毒酪氨酸的ATF4过隐含能够引起肝的皮质醇抵御，而显性性状ATF4（dominant negative-ATF4）能够大幅提高肝胰脏高雅；进一步深入研究证实ATF4对泌尿系统糖代谢的闭环是通过神经系统S6K1以及肝迷走神经信号传递的；另外，本深入研究还证实了ATF4是当实质上细胞质应激引起泌尿系统皮质醇抵御过程当中的关键调控因子。

本深入研究概述了当实质上神经系统ATF4在糖代谢方面的新系统，为深入研究当实质上闭环泌尿系统胰脏高雅提供了一个原先充满信心，并拓宽了当实质上细胞质应激对肝皮质醇抵御的深入研究，珍贵了人们对各个内脏的交互依赖性调控糖代谢的认识，有助于加深人们对乳癌及相关的代谢性疾病发生机制的解读。

该项管理工作获得研究机构院所、农业部以及当中科院等研究机构基金的支持。

与神经系统相关的拓展书本：

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.