Diabetes：郭非凡等揭示下丘脑ATF4管控肝脏胰岛感性的新功能

近日，国际学术论文Diabetes在线发表了中都科院上海生科院营养科学科学研究所郭非凡组的科学研究论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该科学研究阐明了皮质再造转录生物体4 (ATF4) 通过激活线粒体S6K磷酸化(p70 S6K1)，进而诱发锥体肝脏的家兔感伤的小分子机制，阐明了皮质ATF4闭环锥体糖类波形的新功能。

2型肝炎是一种慢开放性糖类开放性疾病，随着贫困水平的日益进一步提高，我国2型肝炎的发病率急速增大。目前关于2型肝炎的科学研究主要集中于都在肝脏等单个循环系统，而各个循环系统的化学键对2型肝炎影响的科学研究较少。实质上神经系统，尤其是皮质，在机体锥体组织的家兔感伤闭环中都起非常重要的诱发作用，近年来已逐渐成为一个科学研究热点。ATF4是CREB家族中都的一个重要成员，前关于ATF4依赖开放性糖类的功能科学研究主要集中于都在锥体组织，例如ATF4 全身敲除小鼠可能会贫血，脂肪减少，可用增大，家兔感伤升高；成骨细胞中都特异开放性敲除ATF4也可能会进一步提高家兔感伤等。但是实质上神经系统中都ATF4是否参与锥体家兔感伤的闭环尚无报道。

郭非凡科学研究小组的名教授张倩等人发现，通过第三脑室切除腺病毒诱导的ATF4过解读并能引起肝脏的甲状腺激素抵抗，而显开放性突变ATF4（dominant negative-ATF4）并能进一步提高肝脏家兔感伤；进一步科学研究证实ATF4对锥体糖糖类的闭环是通过皮质S6K1以及肝脏迷走神经回波传递的；另外，本科学研究还证实了ATF4是实质上核糖体生理反应引起锥体甲状腺激素抵抗步骤中都的关键依赖开放性生物体。

本科学研究阐明了实质上皮质ATF4在糖糖类方面的新功能，为科学研究实质上闭环锥体家兔感伤提供了一个新的前景，并新建了实质上核糖体生理反应对肝脏甲状腺激素抵抗的科学研究，丰富了人们对各个循环系统的化学键依赖开放性糖糖类的认识，借以加深人们对肝炎及之外的糖类开放性疾病发生机制的理解。

该项工作给予国家自然科学基金、科技部以及中都科院等科研基金的支持。

与皮质之外的拓展阅读：

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.