Diabetes：郭非凡等揭示下丘脑ATF4调控肝脏人体内感性的新功能

近日，国际学术期刊Diabetes的网站发表了清华大学上海生科院营养科学研究兼职所郭非凡组的研究兼职论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该研究兼职详述了的中央神经系统活化酪氨酸因子4 (ATF4) 通过酪氨酸线粒体S6K蛋白激酶(p70 S6K1)，进而抑制向外肝细胞的胰脏真挚的化学键机制，推断出了的中央神经系统ATF4适度向外代谢周期性的新功能。

2型冠心病是一种慢官能代谢官能疾病，随着孤独水平的愈加大幅提高，我国2型冠心病的发病率急速增加。目前关于2型冠心病的研究兼职主要之外在肝细胞等单个循环系统，而各个循环系统的耦合对2型冠心病冲击的研究兼职很少。的中央神经系统，相比之下是的中央神经系统，在机体向外组织的胰脏真挚适度中起非常重要的作用，近十年已渐渐成为一个研究兼职热点。ATF4是CREB家族中的一个重要全体成员，以后关于ATF4基因表达代谢的功能研究兼职主要之外在向外组织，例如ATF4 全身敲除小鼠就会贫血，油脂减少，能量消耗增加，胰脏真挚升高；成骨细胞中特异官能敲除ATF4也就会大幅提高胰脏真挚等。但是的中央神经系统中ATF4是否参与向外胰脏真挚的适度已确定报道。

郭非凡研究兼职组的博士生张倩等人发现，通过第三脑室药剂腺病毒介导的ATF4过表达必须招致肝细胞的胰脏素对抗，而显官能甲基化ATF4（dominant negative-ATF4）必须大幅提高肝细胞胰脏真挚；进一步研究兼职证实ATF4对向外糖代谢的适度是通过的中央神经系统S6K1以及肝细胞迷走神经信号传递的；另外，本研究兼职还证实了ATF4是的中央上皮细胞神经细胞招致向外胰脏素对抗过程中的最重要基因表达因子。

本研究兼职推断出了的中央的中央神经系统ATF4在糖代谢方面的新功能，为研究兼职的中央适度向外胰脏真挚提供了一个新前景，并拓宽了的中央上皮细胞神经细胞对肝细胞胰脏素对抗的研究兼职，丰富了人们对各个循环系统的耦合基因表达糖代谢的引介，有助于加深人们对冠心病及关的的代谢官能疾病发生机制的认知。

该项兼职得到国家自然科学投资基金、科技部以及清华大学等科研投资基金的赞同。

与的中央神经系统关的的持续发展阅读：

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.