Diabetes：郭非凡等揭示下丘脑ATF4调控脾脏胰岛感性的新功能

亦同，国际学术期刊Diabetes因特网发表了早先科院上海生科院微量元素科学研究深入研究所姚非凡组的深入研究论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该深入研究阐明了副交感神经再造核糖体系数4 (ATF4) 通过激活亚基S6K色氨酸(p70 S6K1)，进而抑制外周消化系统的胰脏真诚的分子机制，揭示了副交感神经ATF4闭环外周代谢稳态的模组性。

2M-冠心病是一种慢性代谢性疟疾，随着生活素质的日益降低，要务2M-冠心病的发病急速增加。目前关于2M-冠心病的深入研究主要集早先在消化系统等单个肾脏，而各个肾脏的引力对2M-冠心病冲击的深入研究很少。神经系统，众所周知是副交感神经，在飞翼外周组织的胰脏真诚闭环早先起非常重要的作用，近十年已随之成为一个深入研究热点。ATF4是CREB家系早先的一个重要的组织，早先关于ATF4管控代谢的功能性深入研究主要集早先在外周组织，例如ATF4 全身敲除豚鼠会疟疾，脂肪减低，更少增加，胰脏真诚升高；成骨细胞早先特异性敲除ATF4也会降低胰脏真诚等。但是神经系统早先ATF4是否是参与外周胰脏真诚的闭环不得而知报道。

姚非凡深入研究组的博士生张倩等人发现，通过第三脑室注射腺病毒介导的ATF4过表达只能招致消化系统的胰脏素压制，而显性突变ATF4（dominant negative-ATF4）只能降低消化系统胰脏真诚；大幅度深入研究属实ATF4实质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，本深入研究还属实了ATF4是的早先心细胞内表征招致外周胰脏素压制过程早先的关键因素管控系数。

本深入研究揭示了的早先心副交感神经ATF4在糖代谢方面的模组性，为深入研究的早先心闭环外周胰脏真诚共享了一个新的无疑，并新建了的早先心细胞内表征对消化系统胰脏素压制的深入研究，丰富了人们对各个肾脏的引力管控糖代谢的认识，更大幅度随之而来人们对冠心病及之外的代谢性疟疾引发机制的理解。

该项工作获取重点项目、教育部以及早先科院等科研机构基金的拥护。

与副交感神经之外的拓展读物：

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.