Diabetes：郭非凡等揭示下丘脑ATF4调控肝脏胰岛感性的开发人员

近日，国际性学术期刊Diabetes在线发表了国家科委汉口生科院营养科学研究课题所杨非凡三组的研究课题论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该研究课题阐明了副交感神经活化转录因子4 (ATF4) 通过激活线粒体S6K蛋白激酶(p70 S6K1)，进而抑制肺脏肝细胞的口内坦率的分子机制，推断出了副交感神经ATF4可调肺脏代谢稳态的补丁。

2标准型白血病是一种慢连续性代谢连续性病因，随着生活水平的日渐降低，我国2标准型白血病的患病率急速增加。目前关于2标准型白血病的研究课题主要集里面于在肝细胞等单个内脏，而各个内脏的交互起着对2标准型白血病影响的研究课题极少。行政机构神经系统，相比较是副交感神经，在飞翼肺脏三许多组织的口内坦率可调里面起比较重要的起着，近年来已逐渐成为一个研究课题热点。ATF4是CREB家族里面的一个重要成员，在此之前关于ATF4调节代谢的功能研究课题主要集里面于在肺脏三许多组织，例如ATF4 胸部敲除小鼠时会贫血，油脂减少，能量消耗增加，口内坦率升高；成骨细胞里面特异连续性敲除ATF4也时会降低口内坦率等。但是行政机构神经系统里面ATF4是否积极参与肺脏口内坦率的可调尚无新闻报道。

杨非凡研究课题三组的高级工程师张倩等人发现，通过第三血管壁服用腺病毒细胞内的ATF4过强调都能引来肝细胞的生长激素抵抗，而显连续性特异性ATF4（dominant negative-ATF4）都能降低肝细胞口内坦率；进一步研究课题证实ATF4对肺脏糖代谢的可调是通过副交感神经S6K1以及肝细胞迷走神经接收机发送至的；另外，本研究课题还证实了ATF4是行政机构线粒体应激引来肺脏生长激素抵抗处理过程里面的关键调节因子。

本研究课题推断出了行政机构副交感神经ATF4在糖代谢多方面的补丁，为研究课题行政机构可调肺脏口内坦率提供了一个一新机遇，并拓宽了行政机构线粒体应激对肝细胞生长激素抵抗的研究课题，丰富了人们对各个内脏的交互起着调节糖代谢的认识，最大限度加深人们对白血病及关的的代谢连续性病因发生机制的了解。

该项工作给与国家自然科学投资公司、科技部以及国家科委等科研投资公司的支持。

与副交感神经关的的拓展阅读：

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.