Diabetes：郭非凡等揭示下丘脑ATF4调控肝脏胰岛感性的新版本

近日，世界特质学术期刊Diabetes在线发表了国家科委上海生科院营养科学研究成果所刘非凡组的研究成果论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该研究成果概述了神经递质活化转录因子4 (ATF4) 通过激活核糖体S6K蛋白激酶(p70 S6K1)，进而选择性上皮细胞胰脏的肝细胞知特质的底物机制，阐述了神经递质ATF4调节上皮细胞葡萄糖稳态的新内容。

2DF乳癌是一种慢特质葡萄糖特质病因，随着生活水平的日趋大大提高，我国2DF乳癌的发生率急速减小。目前关于2DF乳癌的研究成果主要集当中在胰脏等单个人体器官，而各个人体器官的交互作用对2DF乳癌冲击的研究成果很少。神经递质，相比较是神经递质，在机体上皮细胞组织的肝细胞知特质调节当中起非常不可忽视的作用，持续发展已逐渐成为一个研究成果近来。ATF4是CREB大家族当中的一个不可忽视成员，之前关于ATF4转录葡萄糖的功能研究成果主要集当中在上皮细胞组织，例如ATF4 全身敲除激素亦会疾病，碳水化合物减缓，但会减小，肝细胞知特质升高；成骨细胞当中依赖特质敲除ATF4也亦会大大提高肝细胞知特质等。但是神经递质当中ATF4是否参与上皮细胞肝细胞知特质的调节尚未有媒体报道。

刘非凡研究成果组的研究生张倩等人断定，通过第三脑室针头腺病毒介导的ATF4过表达必需惹来胰脏的肝细胞素抵抗，而显特质突变ATF4（dominant negative-ATF4）必需大大提高胰脏肝细胞知特质；进一步研究成果证明ATF4对上皮细胞糖葡萄糖的调节是通过神经递质S6K1以及胰脏血液循环信号传递信息的；另外，本研究成果还证明了ATF4是行政机关内质网焦虑惹来上皮细胞肝细胞素抵抗过程当中的关键转录因子。

本研究成果阐述了行政机关神经递质ATF4在糖葡萄糖上都的新内容，为研究成果行政机关调节上皮细胞肝细胞知特质包括了一个取而代之前景，并整建了行政机关内质网焦虑对胰脏肝细胞素抵抗的研究成果，多样化了人们对各个人体器官的交互作用转录糖葡萄糖的认识，有助于缓和人们对乳癌及关的的葡萄糖特质病因发生机制的理解。

该项工作获取国家自然科学投资基金、科技部以及国家科委等科研机构投资基金的支持。

与神经递质关的的拓展朗读：

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.