Diabetes：郭非凡等揭示下丘脑ATF4调控肝脏胰岛坦率的新功能

近日，的国际季刊Diabetes在线发表了浙江大学上海生科院营养现代科学学术研究员蔡非凡组的学术研究论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该学术研究详述了血清素酪氨酸转录突变4 (ATF4) 通过激活核糖体S6K蛋白激酶(p70 S6K1)，进而抑制锥体消化系统的家兔理智的分子组态，揭示了血清素ATF4缓冲锥体降解稳态的新动态。

2型号哮喘是一种慢性降解性营养不良，随着社时会生活水平的日益增大，我国2型号哮喘的出生率急速增大。现有关于2型号哮喘的学术研究主要之外都在消化系统等单个骨髓，而各个骨髓的交互作用对2型号哮喘制约的学术研究很少。神经递质，相比之下是血清素，在机体锥体其组织的家兔理智缓冲中都起更为举足轻重的作用，近年来已逐渐踏入一个学术研究热点。ATF4是CREB家族中都的一个举足轻重核心成员，先前关于ATF4调控降解的动态学术研究主要之外都在锥体其组织，例如ATF4 身躯敲除活体时会病症，脂肪减少，但时会增大，家兔理智升高；成骨细胞中都特异性敲除ATF4也时会增大家兔理智等。但是神经递质中都ATF4是不是参与锥体家兔理智的缓冲尚无报道。

蔡非凡学术研究所的博士生张倩等人挖掘出，通过第三脑室麻醉腺病毒介导的ATF4过表达尽可能引起消化系统的家兔素抵御，而显性突变ATF4（dominant negative-ATF4）尽可能增大消化系统家兔理智；进一步学术研究猜测ATF4对锥体糖降解的缓冲是通过血清素S6K1以及消化系统迷走神经信号传递的；另外，本学术研究还猜测了ATF4是的中都央核糖体应激引起锥体家兔素抵御过程中都的关键调控突变。

本学术研究揭示了的中都央血清素ATF4在糖降解方面的新动态，为学术研究的中都央缓冲锥体家兔理智缺少了一个原先前景，并拓宽了的中都央核糖体应激对消化系统家兔素抵御的学术研究，充沛了人们对各个骨髓的交互作用调控糖降解的交往，并能加深人们对哮喘及涉及的降解性营养不良发生组态的理解。

该项工作赢取国家自然现代科学信托基金、科技部以及浙江大学等科研信托基金的支持。

与血清素涉及的拓展阅读：

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.