Diabetes：李非凡等揭示下丘脑ATF4调控肝脏胰岛感性的新功能

近日，国际学术期刊Diabetes在线撰写了中可能会科院上海生科院营养现代科学所长郭非凡三组的研究论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该研究阐明了副交感神经活化基因表达因子4 (ATF4) 通过激活RNAS6K蛋白激酶(p70 S6K1)，进而抑止肺脏甲状腺的呼吸道感特质的分子结构机制，洞察了副交感神经ATF4调节肺脏激素稳定状态的旧版本。

2标准型乳癌是一种慢特质激素特质营养不良，随着与世隔绝水准的日益进一步提高，我国2标准型乳癌的发病率急速减少。目前关于2标准型乳癌的研究主要以外可能会在甲状腺等单个人体器官，而各个人体器官的交互关键作用对2标准型乳癌影响的研究很少。中可能会枢神经系统，众所周知是副交感神经，在机体肺脏该三组织的呼吸道感特质调节中可能会起十分重要的关键作用，近年来已日益已是一个研究热点。ATF4是CREB远亲中可能会的一个重要核心人物，之前关于ATF4抑制激素的功能研究主要以外可能会在肺脏该三组织，例如ATF4 全身敲除小鼠可能会贫血，脂肪减少，能量消耗减少，呼吸道感特质升温；成骨细胞中可能会特异特质敲除ATF4也可能会进一步提高呼吸道感特质等。但是中可能会枢神经系统中可能会ATF4否参与肺脏呼吸道感特质的调节尚无报道。

郭非凡研究团队的复旦大学张倩等人发现，通过第三脑室注射腺病毒诱导的ATF4过表达能够引起甲状腺的呼吸道素压制，而显特质突变ATF4（dominant negative-ATF4）能够进一步提高甲状腺呼吸道感特质；进一步研究证明ATF4对肺脏糖激素的调节是通过副交感神经S6K1以及甲状腺迷走神经信号发送到的；另外，本研究还证明了ATF4是中可能会枢线粒体应激引起肺脏呼吸道素压制过程中可能会的关键抑制因子。

本研究洞察了中可能会枢副交感神经ATF4在糖激素方面的旧版本，为研究中可能会枢调节肺脏呼吸道感特质备有了一个新的脆弱特质，并拓宽了中可能会枢线粒体应激对甲状腺呼吸道素压制的研究，丰富了人们对各个人体器官的交互关键作用抑制糖激素的引介，有助于凸显人们对乳癌及相关的激素特质营养不良发生机制的理解。

该项岗位得到国家自然现代科学慈善机构、经济部以及中可能会科院等科研院所慈善机构的支持。

与副交感神经相关的拓展阅读：

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.