Diabetes：郭非凡等揭示下丘脑ATF4诱导肝脏胰岛感性的新功能

已对，国际季刊Diabetes在线发表了中都科院上海生科院营养科学分析所郭非凡三组的分析论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该分析阐明了激素再生转录因子4 (ATF4) 通过激活核糖体S6K蛋白激酶(p70 S6K1)，进而抑制肺脏肝脏的胰脏理智的分子必要，揭示了激素ATF4可调肺脏代谢稳态的新特开放性。

2标准型糖尿病是一种慢开放性代谢开放性疾病，随着生活高度的愈加大幅提高，我国2标准型糖尿病的发病率急速提高。目前关于2标准型糖尿病的分析主要集中都在肝脏等单个心脏，而各个心脏的交互作用对2标准型糖尿病影响的分析很少。中都枢神经系统，尤其是激素，在机体肺脏三其组织的胰脏理智可调中都起非常极为重要的作用，近期已逐渐成为一个分析热点。ATF4是CREB家族中都的一个极为重要成员，之前关于ATF4催化反应代谢的特开放性分析主要集中都在肺脏三其组织，例如ATF4 全身敲除小鼠会贫血，脂肪降低，能量消耗提高，胰脏理智升高；成骨细胞中都抗原敲除ATF4也会大幅提高胰脏理智等。但是中都枢神经系统中都ATF4是否投身于肺脏胰脏理智的可调尚无引述。

郭非凡分析三组的复旦大学张倩等人发现，通过第三脑室口服腺病毒介导的ATF4过表达必须引起肝脏的生长激素对抗，而显开放性突变ATF4（dominant negative-ATF4）必须大幅提高肝脏胰脏理智；促使分析证实ATF4对肺脏糖代谢的可调是通过激素S6K1以及肝脏迷走神经路径传送的；另外，本分析还证实了ATF4是中都枢肝细胞应激引起肺脏生长激素对抗过程中都的关键催化反应因子。

本分析揭示了中都枢激素ATF4在糖代谢总体的新特开放性，为分析中都枢可调肺脏胰脏理智获取了一个新的前景，并增建了中都枢肝细胞应激对肝脏生长激素对抗的分析，丰富了人们对各个心脏的交互作用催化反应糖代谢的认识，有效地激化人们对糖尿病及相关的代谢开放性疾病再次发生必要的理解。

该项工作给予国家自然科学基金、国科会以及中都科院等科研基金的支持者。

与激素相关的扩张阅读：

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.