Diabetes：徐非凡等揭示下丘脑ATF4调控肝脏胰岛感性的新功能

近日，国际文摘Diabetes在线发表文章了国家科委上海生科院营养科学研究工作所郭非凡组的研究工作论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该研究工作阐释了外周酪氨酸转录因子4 (ATF4) 通过激活核糖体S6K蛋白激酶(p70 S6K1)，进而抑制外周肝细胞的胰脏知普遍性的小分子前提，揭示了外周ATF4缓冲外周代谢稳态的新系统。

2型式高血压是一种慢普遍性代谢普遍性营养不良，随着日常生活高度的日益提高，必将2型式高血压的发病率急速提高。目前关于2型式高血压的研究工作主要集里在肝细胞等单个生殖器官，而各个生殖器官的交互关键作用对2型式高血压影响的研究工作较少。里枢神经系统，偏爱是外周，在机体外周该组织的胰脏知普遍性缓冲里起更加重要的关键作用，近年来已逐渐带进一个研究工作最近。ATF4是CREB后裔里的一个重要成员，之前关于ATF4转录代谢的系统研究工作主要集里在外周该组织，例如ATF4 全身敲除小鼠都会营养不良，脂肪减缓，可用提高，胰脏知普遍性升高；成骨细胞里特异普遍性敲除ATF4也都会提高胰脏知普遍性等。但是里枢神经系统里ATF4是否参与外周胰脏知普遍性的缓冲尚无路透社。

郭非凡研究工作组的名教授张倩等人发现，通过第三脑脊液施用腺病毒内皮细胞的ATF4过表达很难惹来肝细胞的胰脏素对抗，而显普遍性基因ATF4（dominant negative-ATF4）很难提高肝细胞胰脏知普遍性；全面研究工作推测ATF4对外周糖代谢的缓冲是通过外周S6K1以及肝细胞迷走神经信号传递的；另外，本研究工作还推测了ATF4是里枢溶酶体应激惹来外周胰脏素对抗过程里的不可或缺转录因子。

本研究工作揭示了里枢外周ATF4在糖代谢方面的新系统，为研究工作里枢缓冲外周胰脏知普遍性提供了一个新前景，并整建了里枢溶酶体应激对肝细胞胰脏素对抗的研究工作，充沛了人们对各个生殖器官的交互关键作用转录糖代谢的认识，最大限度缓和人们对高血压及相关的代谢普遍性营养不良发生前提的理解。

该项工作给与国家自然科学基金、科技部以及国家科委等科研基金的全力支持。

与外周相关的拓展朗读：

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.