Diabetes：郭非凡等揭示下丘脑ATF4调控肝脏家兔感性的新功能

据悉，国际刊物Diabetes在线发表了中所科院上海生科院营养科学分析所李非凡组的分析篇文章“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该分析探究了副交感神经活化转录因子4 (ATF4) 通过抑制核糖体S6K色氨酸(p70 S6K1)，进而抑制外周消化系统的家兔坦率的分子必要，洞察了副交感神经ATF4闭环外周代谢数学模型的新功用。

2标准型肝炎是一种慢性代谢性疾病，随着家庭水平的日益减低，我国2标准型肝炎的发病率急速增加。现在关于2标准型肝炎的分析主要密集所在消化系统等单个脑部，而各个脑部的交互作用对2标准型肝炎影响的分析很少。中所枢神经系统，众所周知是副交感神经，在各部位外周秘密组织的家兔坦率闭环中所起非常重要的作用，近年来已逐渐成为一个分析热点。ATF4是CREB家族中所的一个重要团员，之前关于ATF4抑制代谢的功用分析主要密集所在外周秘密组织，例如ATF4 手脚敲除小鼠不会疾病，脂肪减少，能量消耗增加，家兔坦率急剧下降；成骨细胞中所抗体敲除ATF4也不会减低家兔坦率等。但是中所枢神经系统中所ATF4是否进行外周家兔坦率的闭环尚有路透社。

李非凡分析组的北京师范大学张倩等人发掘出，通过第三脑室静脉注射腺病毒内皮细胞的ATF4过表达都能引起消化系统的家兔素对抗，而显性性状ATF4（dominant negative-ATF4）都能减低消化系统家兔坦率；进一步分析证实ATF4实质上周糖代谢的闭环是通过副交感神经S6K1以及消化系统迷走神经信号传递的；另外，本分析还证实了ATF4是中所枢上皮细胞焦虑引起外周家兔素对抗过程中所的关键抑制因子。

本分析洞察了中所枢副交感神经ATF4在糖代谢层面的新功用，为分析中所枢闭环外周家兔坦率发放了一个新的大环境，并拓宽了中所枢上皮细胞焦虑对消化系统家兔素对抗的分析，丰富了人们对各个脑部的交互作用抑制糖代谢的了解，并能激化人们对肝炎及无关的代谢性疾病发生必要的理解。

该项文书工作得到重点项目、科技部以及中所科院等科研人员基金的支持。

与副交感神经无关的拓展读到：

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.