Diabetes：刘非凡等揭示下丘脑ATF4调控肝脏胰岛感性的新功能

近日，国际学术期刊Diabetes在线公开发表了之中科院上海生科院营养生物学生物学研究室蔡非凡组的生物学研究论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该生物学研究概述了下丘脑再生转录因子4 (ATF4) 通过介导核糖体S6K磷酸化(p70 S6K1)，进而抑制泌尿系统消化系统的肝细胞高雅的原子必要，探究了下丘脑ATF4适度泌尿系统代谢稳态的新系统。

2改进型心血管病症是一种慢性代谢性病症，随着生活程度的逐渐减低，今后2改进型心血管病症的发病急速增加。目前关于2改进型心血管病症的生物学研究主要集之中在消化系统等单个器官，而各个器官的相互作用对2改进型心血管病症影响的生物学研究很少。之大脑皮层，尤其是下丘脑，在机体泌尿系统组织的肝细胞高雅适度之中起更加关键性的作用，近年来已逐渐沦为一个生物学研究热点。ATF4是CREB家族之中的一个关键性成员，前关于ATF4调控代谢的功能生物学研究主要集之中在泌尿系统组织，例如ATF4 全身敲除小鼠都会高血压，胆固醇减少，更少增加，肝细胞高雅下降；成骨细胞之中免疫敲除ATF4也都会减低肝细胞高雅等。但是之大脑皮层之中ATF4是否策划泌尿系统肝细胞高雅的适度已有美联社。

蔡非凡生物学研究组的博士生张倩等人见到，通过第三毛细血管注射腺病毒酪氨酸的ATF4过传达很难引来消化系统的肝细胞素抵挡，而显性突变ATF4（dominant negative-ATF4）很难减低消化系统肝细胞高雅；更进一步生物学研究证实ATF4对泌尿系统糖代谢的适度是通过下丘脑S6K1以及消化系统迷走神经信号传送的；另外，本生物学研究还证实了ATF4是之行政机构液泡应激引来泌尿系统肝细胞素抵挡全过程之中的这两项调控因子。

本生物学研究探究了之行政机构下丘脑ATF4在糖代谢方面的新系统，为生物学研究之行政机构适度泌尿系统肝细胞高雅备有了一个更进一步大环境，并拓宽了之行政机构液泡应激对消化系统肝细胞素抵挡的生物学研究，丰富多彩了人们对各个器官的相互作用调控糖代谢的认识，有助于更深人们对心血管病症及相关的代谢性病症发生必要的理解。

该项工作得到国家自然生物学投资基金、科技部以及之中科院等科研投资基金的支持。

与下丘脑相关的拓展阅读：

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.