Diabetes：郭非凡等揭示下丘脑ATF4转录肝脏胰岛感性的新功能

近日，国际上医学期刊Diabetes在线发表了中可能会科院厦门生科院营养科学分析所郭非凡两组的分析论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该分析阐明了中枢神经系统激活转录系数4 (ATF4) 通过激活核糖体S6K磷酸化(p70 S6K1)，进而诱发上皮细胞肝脏的人体内理智的分子结构选择性，洞察了中枢神经系统ATF4闭环上皮细胞糖类一个系统的新功能。

2型冠心病是一种慢性糖类性疟疾，随着生活水平的日益提高，中华民族2型冠心病的发病率急速增加。目前关于2型冠心病的分析主要比较大可能会在肝脏等单个器官，而各个器官的碰撞对2型冠心病负面影响的分析很少。中可能会枢神经系统，尤其是中枢神经系统，在机上皮细胞的两组织的人体内理智闭环中可能会起非常最主要的作用，近年来已逐渐成一个分析热点。ATF4是CREB家族中可能会的一个最主要成员，之前关于ATF4诱导糖类的功能分析主要比较大可能会在上皮细胞的两组织，例如ATF4 上半身敲除小鼠可能会贫血，脂肪减少，能量消耗增加，人体内理智升高；成骨细胞中可能会特异性敲除ATF4也可能会提高人体内理智等。但是中可能会枢神经系统中可能会ATF4是否参与上皮细胞人体内理智的闭环尚无报道。

郭非凡分析两组的副教授张倩等人发现，通过第三血管壁注射腺病毒内源性的ATF4过理解能够造成肝脏的人体内素压制，而显性突变ATF4（dominant negative-ATF4）能够提高肝脏人体内理智；全面分析证实ATF4对上皮细胞糖糖类的闭环是通过中枢神经系统S6K1以及肝脏行政机构神经路径传递的；另外，本分析还证实了ATF4是中可能会枢核糖体应激造成上皮细胞人体内素压制过程中可能会的关键诱导系数。

本分析洞察了中可能会枢中枢神经系统ATF4在糖糖类全面性的新功能，为分析中可能会枢闭环上皮细胞人体内理智提供了一个新的机遇，并完工后了中可能会枢核糖体应激对肝脏人体内素压制的分析，丰富了人们对各个器官的碰撞诱导糖糖类的认识，有助于随之而来人们对冠心病及关的的糖类性疟疾发生选择性的理解。

该项社可能会活动得到国家科技进步奖、科技部以及中可能会科院等科研基金的支持。

与中枢神经系统关的的拓展阅读：

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.