Diabetes：郭非凡等阐明下丘脑ATF4调控肝脏胰岛感性的新功能

全因，国际JournalDiabetes在线发表了之北京航空航天大学上海生科院营养物理数据分析所郭非凡组的数据分析博士论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该数据分析洞察了下丘脑增殖酪氨酸系数4 (ATF4) 通过激活核糖体S6K蛋白激酶(p70 S6K1)，进而抑制上皮细胞消化系统的胰脏高雅的分子结构选择性，阐释了下丘脑ATF4闭环上皮细胞降解稳态的新功能。

2型癌症是一种慢性降解性性疾病，随着生活水平的日益增加，我国2型癌症的发病率急速增加。目前关于2型癌症的数据分析主要分散在消化系统等单个循环系统，而各个循环系统的交互依赖性对2型癌症影响的数据分析很少。之实质上神经系统，尤其是下丘脑，在舰载机上皮细胞组织的胰脏高雅闭环之中起非常重要的依赖性，近年来已逐渐成为一个数据分析热点。ATF4是CREB家族之中的一个重要小团体，之前关于ATF4依赖性降解的功能数据分析主要分散在上皮细胞组织，例如ATF4 全身敲除动物模型会冠心病，脂肪减小，除此以外增加，胰脏高雅升高；成骨细胞之中特异性敲除ATF4也会增加胰脏高雅等。但是之实质上神经系统之中ATF4是否积极参与上皮细胞胰脏高雅的闭环尚无报道。

郭非凡数据分析组的博士生张倩等人发现，通过第三脑室施用腺病毒介导的ATF4过表达能够激起消化系统的胰脏素抗击，而显性突变ATF4（dominant negative-ATF4）能够增加消化系统胰脏高雅；进一步数据分析证实ATF4对上皮细胞糖降解的闭环是通过下丘脑S6K1以及消化系统腔静脉信号引导的；另外，本数据分析还证实了ATF4是之实质上上皮细胞诱发激起上皮细胞胰脏素抗击过程之中的关键依赖性系数。

本数据分析阐释了之实质上下丘脑ATF4在糖降解方面的新功能，为数据分析之实质上闭环上皮细胞胰脏高雅提供了一个在此之后前景，并拓宽了之实质上上皮细胞诱发对消化系统胰脏素抗击的数据分析，丰富了人们对各个循环系统的交互依赖性依赖性糖降解的认识，有助于加深人们对癌症及就其的降解性性疾病发生选择性的理解。

该项工作得到国家自然物理信托基金、科技部以及之北京航空航天大学等科研信托基金的大力支持。

与下丘脑就其的扩大阅读：

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.