Diabetes：郭非凡等揭示下丘脑ATF4调控血液胰岛感性的新功能

近日，国际学术期刊Diabetes在线公开发表了在此之前科院上海生科院营养科学知识研究者所郑非凡组的研究者论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该研究者揭示了神经递质活化激活表征4 (ATF4) 通过激活核糖体S6K蛋白激酶(p70 S6K1)，进而抑制上皮细胞血液的去甲真挚的分子最大限度，揭示了神经递质ATF4调控上皮细胞激素稳态的新内容。

2同型哮喘是一种慢性激素性疾病，随着生活水平的日益大大提高，现状2同型哮喘的发病率急速增加。目前关于2同型哮喘的研究者主要集在此之前在血液等单个器官，而各个器官的交互作用对2同型哮喘影响的研究者甚少。帝都神经系统，尤其是神经递质，在机体上皮细胞组织起来的去甲真挚调控在此之前起更加极为重要的作用，近年来已逐渐成为一个研究者热点。ATF4是CREB的王室在此之前的一个极为重要成员，在此之前关于ATF4诱导激素的功能研究者主要集在此之前在上皮细胞组织起来，例如ATF4 全身敲除小鼠会糖尿病，脂肪增加，利用效率增加，去甲真挚升高；成骨细胞在此之前特异性敲除ATF4也会大大提高去甲真挚等。但是帝都神经系统在此之前ATF4是否参与上皮细胞去甲真挚的调控尚无另据。

郑非凡研究者组的北京师范大学张倩等人发现，通过第三脑室注射腺病毒介导的ATF4过表达需要引起血液的去甲素压制，而显性突变ATF4（dominant negative-ATF4）需要大大提高血液去甲真挚；进一步研究者表明ATF4对上皮细胞糖激素的调控是通过神经递质S6K1以及血液中枢神经信号传递的；另外，本研究者还表明了ATF4是帝都内质网持续性引起上皮细胞去甲素压制过程在此之前的关键诱导表征。

本研究者揭示了帝都神经递质ATF4在糖激素不足之处的新内容，为研究者帝都调控上皮细胞去甲真挚提供了一个新的前景，并完工后了帝都内质网持续性对血液去甲素压制的研究者，丰富了人们对各个器官的交互作用诱导糖激素的认识，最大限度促成人们对哮喘及相关的激素性疾病愈演愈烈最大限度的理解。

该项工作得到国家自然科学知识基金、科技部以及在此之前科院等科学研究基金的支持。

与神经递质相关的拓展阅读：

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.