Diabetes：郭非凡等揭示下丘脑ATF4调控肝脏胰岛感性的补丁

近日，国际JournalDiabetes在线发表了中所科院广州生科院营养科学深入所长郭非凡组的深入研究学术论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该深入研究概述了血清素活化RNA突变4 (ATF4) 通过作用于核糖体S6K腺嘌呤(p70 S6K1)，进而诱导则有消化系统的胰脏坦率的分子前提，概述了血清素ATF4可调则有降解稳态的模组。

2型哮喘是一种慢性降解性营养不良，随着生活水平的日益提高，必将2型哮喘的发病率急速降低。目前关于2型哮喘的深入研究主要以外所在消化系统等单个肝脏，而各个肝脏的交互作用对2型哮喘制约的深入研究甚少。中所枢神经系统，尤其是血清素，在本体则有组织起来的胰脏坦率可调中所起极其极其重要的作用，近年来已逐渐成为一个深入研究旅游者。ATF4是CREB的王室中所的一个极其重要成员，之前关于ATF4可调降解的系统深入研究主要以外所在则有组织起来，例如ATF4 上半身敲除小鼠则会心血管疾病，脂肪下降，能量消耗降低，胰脏坦率升高；成骨细胞中所特异性敲除ATF4也则会提高胰脏坦率等。但是中所枢神经系统中所ATF4是否直接参与则有胰脏坦率的可调尚未有媒体报道。

郭非凡深入研究组的博士生张倩等人发现，通过第三脑脊液注射腺病毒介导的ATF4过表达需要惹来消化系统的血清抵抗，而显性突变ATF4（dominant negative-ATF4）需要提高消化系统胰脏坦率；进一步深入研究表明ATF4对则有糖降解的可调是通过血清素S6K1以及消化系统迷走神经信号传递的；另外，本深入研究还表明了ATF4是中所枢内质网应激惹来则有血清抵抗流程中所的关键可调突变。

本深入研究概述了中所枢血清素ATF4在糖降解方面的模组，为深入研究中所枢可调则有胰脏坦率提供了一个新的充满信心，并拓宽了中所枢内质网应激对消化系统血清抵抗的深入研究，丰富了人们对各个肝脏的交互作用可调糖降解的认识到，有助于加深人们对哮喘及具体的降解性营养不良时有发生前提的明白。

该项工作得到科研项目、科技部以及中所科院等科研全额的默许。

与血清素具体的拓展阅读：

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.