Diabetes：郭非凡等揭示下丘脑ATF4调控肝脏肾脏感性的新功能

近日，国际学术期刊Diabetes网络服务发表了中科院上海生科院营养科学深入研究所郭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”。该深入研究探究了神经递质活化转录表征4 (ATF4) 通过激活核糖体S6K蛋白激酶(p70 S6K1)，进而选择性肺脏骨髓的口内知性的大分子机制，了解到了神经递质ATF4调控肺脏激素稳定状态的新功能。

2M-糖尿病是一种慢性激素性病症，随着日常生活高水平的日益提高，现状2M-糖尿病的发病率急速上升。目前关于2M-糖尿病的深入研究主要集中在骨髓等单个内脏，而各个内脏的交互作用对2M-糖尿病受到影响的深入研究很少。行政机构神经系统，尤其是神经递质，在机体肺脏组织的口内知性调控中起非常重要的作用，近年来已逐渐成为一个深入研究邻近地区。ATF4是CREB家族中的一个重要成员，之前关于ATF4催化反应激素的功能深入研究主要集中在肺脏组织，例如ATF4 全身敲除动物模型会病症，脂肪减少，能量消耗上升，口内知性升高；成骨细胞中免疫敲除ATF4也会提高口内知性等。但是行政机构神经系统中ATF4是否参与肺脏口内知性的调控尚无媒体报道。

郭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过表达都能引来骨髓的甲状腺激素抵抗，而显性突变ATF4（dominant negative-ATF4）都能提高骨髓口内知性；进一步深入研究证实ATF4对肺脏糖激素的调控是通过神经递质S6K1以及骨髓迷走神经信号引导的；另外，本深入研究还证实了ATF4是行政机构内质网凋亡引来肺脏甲状腺激素抵抗过程中的最重要催化反应表征。

本深入研究了解到了行政机构神经递质ATF4在糖激素方面的新功能，为深入研究行政机构调控肺脏口内知性给予了一个取而代之前景，并拓宽了行政机构内质网凋亡对骨髓甲状腺激素抵抗的深入研究，丰富了人们对各个内脏的交互作用催化反应糖激素的认识，有助于加深人们对糖尿病及之外的激素性病症发生机制的解读。

该项工作得到国家自然科学该基金会、科技部以及中科院等科研机构该基金会的反对。

与神经递质之外的拓展阅读：

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.