Diabetes：郭非凡等揭示下丘脑ATF4抑制肝脏胰岛感性的新功能

据悉，国际上学术期刊Diabetes在线撰写了国家科委上海生科院营养科学研究院蔡非凡四组的研究科学论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该研究阐释了中枢神经活化转录因子4 (ATF4) 通过激活亚基S6K蛋白激酶(p70 S6K1)，进而抑制向外肝脏的肝细胞特质的分子前提，探究了中枢神经ATF4可调向外糖类参量的新功能。

2改型心血管疾病是一种慢性糖类性疾病，随着生活水平的日趋提高，我国2改型心血管疾病的发病率急速缩减。目前关于2改型心血管疾病的研究主要大部分在肝脏等单个循环系统，而各个循环系统的交互作用对2改型心血管疾病影响的研究很少。的中央神经系统，特别是在是中枢神经，在机体向外四组织的肝细胞特质可调中起非常关键的作用，近年来已逐渐被选为一个研究同类改型。ATF4是CREB家族中的一个关键成员，前关于ATF4调控糖类的功能研究主要大部分在向外四组织，例如ATF4 上半身敲除果蝇会贫血，脂肪减低，能量消耗缩减，肝细胞特质上升时；成骨细胞中特异性敲除ATF4也会提高肝细胞特质等。但是的中央神经系统中ATF4否参与向外肝细胞特质的可调尚无报道。

蔡非凡研究四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过表达并能引发肝脏的肝细胞素对抗，而显性突变ATF4（dominant negative-ATF4）并能提高肝脏肝细胞特质；进一步研究证实ATF4对向外糖糖类的可调是通过中枢神经S6K1以及肝脏迷走神经路径传递的；另外，本研究还证实了ATF4是的中央细胞内应激引发向外肝细胞素对抗过程中的关键调控因子。

本研究探究了的中央中枢神经ATF4在糖糖类方面的新功能，为研究的中央可调向外肝细胞特质提供了一个新的前景，并拓宽了的中央细胞内应激对肝脏肝细胞素对抗的研究，多样化了人们对各个循环系统的交互作用调控糖糖类的认识，有助于加深人们对心血管疾病及关的的糖类性疾病发生前提的理解。

该项工作得到国家自然科学Fund、科技部以及国家科委等科研机构Fund的背书。

与中枢神经关的的拓展写作：

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.