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，国际上学术期刊Diabetes网络刊载了当中科院上海生科院营养科学研究成果所郭非凡组的研究成果科学论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该研究成果阐明了激素活化RNA因子4 (ATF4) 通过激活核糖体S6K蛋白激酶(p70 S6K1)，进而诱发肺脏肝的胰脏高雅的分子前提，揭示了激素ATF4适度肺脏代谢一个系统的新机制。

2改型癌症是一种慢性代谢性病症，随着生活水平的日益提升，法制2改型癌症的感染率急速提高。目前关于2改型癌症的研究成果主要集当中在肝等单个脑部，而各个脑部的作用力对2改型癌症不良影响的研究成果很少。当帝都神经系统，偏爱是激素，在机体肺脏组织的胰脏高雅适度当中起非常极其重要的作用，近年来已逐渐视作一个研究成果热点。ATF4是CREB大家族当中的一个极其重要成员，此前关于ATF4依赖性代谢的机制研究成果主要集当中在肺脏组织，例如ATF4 身躯敲除小鼠会贫血，脂肪减少，能量消耗提高，胰脏高雅升高；成骨细胞当中基因表达敲除ATF4也会提升胰脏高雅等。但是当帝都神经系统当中ATF4是否参与肺脏胰脏高雅的适度尚有报道。

郭非凡研究成果组的博士生张倩等人推测，通过第三脑室注射腺病毒介导的ATF4过表达都能造成了肝的血糖抵御，而显性等位基因ATF4（dominant negative-ATF4）都能提升肝胰脏高雅；进一步研究成果证实ATF4今后周糖代谢的适度是通过激素S6K1以及肝血液循环信号传递的；另外，本研究成果还证实了ATF4是当帝都细胞质应激造成了肺脏血糖抵御过程当中的关键依赖性因子。

本研究成果揭示了当帝都激素ATF4在糖代谢方面的新机制，为研究成果当帝都适度肺脏胰脏高雅提供了一个新前景，并扩宽了当帝都细胞质应激对肝血糖抵御的研究成果，丰富了人们对各个脑部的作用力依赖性糖代谢的熟识，最大限度加深人们对癌症及系统性的代谢性病症发生前提的理解。

该项工作得到科研机构人员、行政院国家科学委员会以及当中科院等科研机构基金的全力支持。

与激素系统性的拓展阅读：

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.