Diabetes：郭非凡等说明了下丘脑ATF4调控肝脏胰岛感性的新功能

全因，国际刊物Diabetes在线发表了先前科院上海生科院营养自然科学研究成果所郭非凡一组的研究成果论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该研究成果说明了皮质转化mRNA生物体4 (ATF4) 通过诱导核糖体S6K原核(p70 S6K1)，进而抑制则有胰脏的去甲坦率的化学键机制，探究了皮质ATF4恒定则有代谢稳态的新动态。

2标准型糖尿病是一种慢性代谢性营养不良，随着日常生活水平的日益增加，我国2标准型糖尿病的发病率急速减小。目前关于2标准型糖尿病的研究成果主要集先前在胰脏等单个心脏，而各个心脏的交互发挥作用对2标准型糖尿病严重影响的研究成果很少。的先前心神经系统，众所周知是皮质，在机体则有一组织的去甲坦率恒定先前起非常重要的发挥作用，持续发展已渐渐成为一个研究成果版块。ATF4是CREB家族先前的一个重要小团体，先前关于ATF4诱导代谢的动态研究成果主要集先前在则有一组织，例如ATF4 全身敲除小鼠会肾病，脂肪减少，能量消耗减小，去甲坦率急剧下降；成骨细胞先前特异性敲除ATF4也会增加去甲坦率等。但是的先前心神经系统先前ATF4是否参加则有去甲坦率的恒定尚无报道。

郭非凡研究成果一组的博士生张倩等人发现，通过第三脑室麻醉腺病毒诱导的ATF4过强调能够引起胰脏的去甲素抵抗，而显性突变ATF4（dominant negative-ATF4）能够增加胰脏去甲坦率；进一步研究成果猜测ATF4对则有糖代谢的恒定是通过皮质S6K1以及胰脏迷走神经信号传递的；另外，本研究成果还猜测了ATF4是的先前心内质网焦虑引起则有去甲素抵抗更进一步先前的关键诱导生物体。

本研究成果探究了的先前心皮质ATF4在糖代谢方面的新动态，为研究成果的先前心恒定则有去甲坦率共享了一个新的现状，并拓宽了的先前心内质网焦虑对胰脏去甲素抵抗的研究成果，丰富了人们对各个心脏的交互发挥作用诱导糖代谢的了解，更进一步加深人们对糖尿病及涉及的代谢性营养不良发生机制的理解。

该项工作得到国家自然自然科学投资公司、科技部以及先前科院等科研成果投资公司的支持。

与皮质涉及的扩大阅读：

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.