Diabetes：郭非凡等揭示下丘脑ATF4调控肝脏胰岛感性的插件

近日，国际JournalDiabetes在线发表了中科院汉口生科院营养科学知识数据分析所郭非凡组的数据分析论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该数据分析阐明了的中心神经活化转录因子4 (ATF4) 通过激活核糖体S6K蛋白激酶(p70 S6K1)，进而选择性骨骼肌肝细胞的去甲情感的分子机制，推断出了的中心神经ATF4诱导骨骼肌细胞内数学模M-的新机制。

2M-糖尿病是一种慢性细胞内性疾病，随着生活水平的日益降低，我国2M-糖尿病的发病率急速降低。目前关于2M-糖尿病的数据分析主要之外在肝细胞等单个肾脏，而各个肾脏的交互作用对2M-糖尿病影响的数据分析很少。的中心神经系统，尤其是的中心神经，在EVA骨骼肌的组织的去甲情感诱导中起非常重要的作用，近年来已逐渐成为一个数据分析热点。ATF4是CREB远亲中的一个重要领导者，前关于ATF4诱导细胞内的机制数据分析主要之外在骨骼肌的组织，例如ATF4 脸部敲除小鼠但会贫血，脂肪减少，利用效率降低，去甲情感升高；成骨细胞中特异性敲除ATF4也但会降低去甲情感等。但是的中心神经系统中ATF4是否加入骨骼肌去甲情感的诱导尚无报道。

郭非凡数据分析组的博士生张倩等人发现，通过第三横膈膜注射腺病毒介导的ATF4过表达出来并不需要引起肝细胞的抗生素反击，而显性突变ATF4（dominant negative-ATF4）并不需要降低肝细胞去甲情感；进一步数据分析断定ATF4对骨骼肌糖细胞内的诱导是通过的中心神经S6K1以及肝细胞迷走神经路径传输的；另外，本数据分析还断定了ATF4是的中心线粒体应激引起骨骼肌抗生素反击流程中的关键诱导因子。

本数据分析推断出了的中心的中心神经ATF4在糖细胞内方面的新机制，为数据分析的中心诱导骨骼肌去甲情感提供了一个属于自己大环境，并拓宽了的中心线粒体应激对肝细胞抗生素反击的数据分析，珍贵了人们对各个肾脏的交互作用诱导糖细胞内的认识，有助于加深人们对糖尿病及相关的细胞内性疾病再次发生机制的理解。

该项临时工获得国家自然科学知识基金、国立清华大学以及中科院等科研基金的支持。

与的中心神经相关的拓展阅读：

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.