Diabetes：郭非凡等揭示下丘脑ATF4调控肝脏肝细胞感性的新功能

亦同，国际JournalDiabetes离线发表了上海交通大学上海生科院营养科学知识研究成果所陈非凡第三组的研究成果专著“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该研究成果阐明了副交感神经活化酪氨酸突变4 (ATF4) 通过激活核糖体S6K蛋白激酶(p70 S6K1)，进而抑制功用肺脏肝细胞的肾脏理智的分子前提，揭示了副交感神经ATF4抑制肺脏糖类稳态的开发人员。

2型式心血管疾病是一种慢性糖类性疾病，随着生活准确度的日益大大提高，我国2型式心血管疾病的发病率急速增高。目前关于2型式心血管疾病的研究成果主要大部分但会在肝细胞等单个器官，而各个器官的震荡对2型式心血管疾病严重影响的研究成果很少。大脑，尤其是副交感神经，在机体肺脏第三组织的肾脏理智抑制中但会起相当不可或缺的功用，近年来已日渐带进一个研究成果热点。ATF4是CREB家族中但会的一个不可或缺成员，之前关于ATF4催化反应糖类的功能研究成果主要大部分但会在肺脏第三组织，例如ATF4 全身敲除小鼠但会病症，脂肪增大，能源消耗增高，肾脏理智升高；成骨细胞中但会抗原敲除ATF4也但会大大提高肾脏理智等。但是大脑中但会ATF4有否加入肺脏肾脏理智的抑制尚无报道。

陈非凡研究成果第三组的高级工程师张倩等人推测，通过第三脑室注射腺病毒介导的ATF4过表示只能引起肝细胞的肾脏素顽强抵抗，而显性突变ATF4（dominant negative-ATF4）只能大大提高肝细胞肾脏理智；更进一步研究成果猜测ATF4对肺脏糖糖类的抑制是通过副交感神经S6K1以及肝细胞消化道频谱传递的；另外，本研究成果还猜测了ATF4是中但会枢肝细胞应激引起肺脏肾脏素顽强抵抗过程中但会的这两项催化反应突变。

本研究成果揭示了中但会枢副交感神经ATF4在糖糖类方面的开发人员，为研究成果中但会枢抑制肺脏肾脏理智共享了一个新的前景，并完工后了中但会枢肝细胞应激对肝细胞肾脏素顽强抵抗的研究成果，丰沛了人们对各个器官的震荡催化反应糖糖类的认识，有助加深人们对心血管疾病及相关的糖类性疾病发生前提的解读。

该项工作受益国家自然科学知识投资公司、国家科委以及上海交通大学等科研成果投资公司的赞同。

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.