Diabetes：郭非凡等揭示下丘脑ATF4调控胰脏胰岛感性的新功能

近日，国际学术期刊Diabetes应用软件发表了清华大学上海生科院营养科学研究工作所邵非凡第一组的研究工作论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该研究工作洞察了血清素活化激活q4 (ATF4) 通过激活核糖体S6K蛋白激酶(p70 S6K1)，进而抑制锥体骨髓的肝细胞真诚的分子最大限度，探究了血清素ATF4调控锥体代谢稳态的新机能。

2型式肝炎是一种慢性代谢性疾病，随着生活水平的日趋大大提高，我国2型式肝炎的发病率急速缩减。目前关于2型式肝炎的研究工作主要分散会在骨髓等单个肾脏，而各个肾脏的起到力对2型式肝炎冲击的研究工作并不多。实质上神经系统，尤其是血清素，在机体锥体秘密第一组织的肝细胞真诚调控中会起极其最主要的起到，近年来已渐渐踏入一个研究工作版块。ATF4是CREB家族中会的一个最主要团员，之前关于ATF4催化反应代谢的机能研究工作主要分散会在锥体秘密第一组织，例如ATF4 全身敲除小鼠会贫血，脂肪减少，能量消耗缩减，肝细胞真诚下降；成骨细胞中会甲基化敲除ATF4也会大大提高肝细胞真诚等。但是实质上神经系统中会ATF4否加入锥体肝细胞真诚的调控尚未有报道。

邵非凡研究工作第一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过强调必需招致骨髓的血糖压制，而显性特异性ATF4（dominant negative-ATF4）必需大大提高骨髓肝细胞真诚；进一步研究工作表明ATF4对锥体糖代谢的调控是通过血清素S6K1以及骨髓脑干瞬时传递的；另外，本研究工作还表明了ATF4是实质上内质网持续性招致锥体血糖压制过程中会的关键催化反应q。

本研究工作探究了实质上血清素ATF4在糖代谢多方面的新机能，为研究工作实质上调控锥体肝细胞真诚获取了一个新的前景，并拓宽了实质上内质网持续性对骨髓血糖压制的研究工作，丰沛了人们对各个肾脏的起到力催化反应糖代谢的认识，最大限度加深人们对肝炎及就其的代谢性疾病起因最大限度的忽略。

该项工作得到国家自然科学全额、科技部以及清华大学等科研院所全额的支持。

与血清素就其的拓展写出：

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.