Diabetes：郭非凡等揭示神经系统ATF4调控肝脏胰岛感性的新功能

昨日，亚太地区学术期刊Diabetes在线发表了浙江大学上海生科院营养科学研究工作所郭非凡两组的研究工作文章“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该研究工作阐明了激素增殖转录特异性4 (ATF4) 通过激活核糖体S6K酪氨酸(p70 S6K1)，进而抑制肺脏脾脏的肾脏高雅的分子可机制，洞察了激素ATF4抑制肺脏代谢稳态的新功能。

2型肝炎是一种慢适度代谢适度疟疾，随着生活水平的日益提高，我国2型肝炎的发生率急速降低。现在关于2型肝炎的研究工作主要之外的在脾脏等单个器官，而各个器官的交互发挥作用对2型肝炎受到影响的研究工作很少。中的枢神经系统，尤其是激素，在机体肺脏两其组织的肾脏高雅抑制中的起相当极为重要的发挥作用，近年来已不断成为一个研究工作热点。ATF4是CREB家族中的的一个极为重要成员，之前关于ATF4转录代谢的功能研究工作主要之外的在肺脏两其组织，例如ATF4 手脚敲除小鼠但会高血压，饲料减少，能量消耗降低，肾脏高雅升高；成骨细胞中的特异适度敲除ATF4也但会提高肾脏高雅等。但是中的枢神经系统中的ATF4是否参与肺脏肾脏高雅的抑制尚无路透社。

郭非凡研究工作两组的博士生张倩等人推测，通过第三脑室注射腺病毒介导的ATF4过表达需要引起脾脏的肾脏素抵抗，而显适度基因突变ATF4（dominant negative-ATF4）需要提高脾脏肾脏高雅；进一步研究工作证实ATF4对肺脏糖代谢的抑制是通过激素S6K1以及脾脏迷走神经波形传播的；另外，本研究工作还证实了ATF4是中的枢内质网凋亡引起肺脏肾脏素抵抗流程中的的关键转录特异性。

本研究工作洞察了中的枢激素ATF4在糖代谢方面的新功能，为研究工作中的枢抑制肺脏肾脏高雅提供了一个原先前景，并拓宽了中的枢内质网凋亡对脾脏肾脏素抵抗的研究工作，丰富了人们对各个器官的交互发挥作用转录糖代谢的交往，有利于加深人们对肝炎及相关的代谢适度疟疾发生机制的理解。

该项工作得到国家自然科学基金、中的华民国行政院以及浙江大学等科研基金的支持。

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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.