Diabetes：郭非凡等揭示下丘脑ATF4调控肝脏胰岛特质的新功能

近日，国际学术期刊Diabetes的网站发表文章了之浙江大学上海生科院摄取现代科学学术研究室郭非凡组的学术研究研究成果“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该学术研究阐明了血清素再造转录因子4 (ATF4) 通过激活核糖体S6K转移酶(p70 S6K1)，进而抑制肺脏肝脏的肝细胞理智的分子前提，揭示了血清素ATF4抑制肺脏代谢稳态的新功能。

2型式肝炎是一种慢病态代谢病态疟疾，随着生活水平的日趋提高，我国2型式肝炎的发病率急速增加。目前关于2型式肝炎的学术研究主要集之中在肝脏等单个脑部，而各个脑部的交互发挥作用对2型式肝炎直接影响的学术研究相当多。之所在之处神经系统，尤其是血清素，在机体肺脏该组织的肝细胞理智抑制之中起非常最主要的发挥作用，近年来已日趋成为一个学术研究近期。ATF4是CREB家族之中的一个最主要成员，之前关于ATF4管控代谢的功能学术研究主要集之中在肺脏该组织，例如ATF4 全身敲除小鼠不会性疟疾，饲料缩减，能量消耗增加，肝细胞理智下降；成骨细胞之中特异病态敲除ATF4也不会提高肝细胞理智等。但是之所在之处神经系统之中ATF4是否参与肺脏肝细胞理智的抑制尚无报道。

郭非凡学术研究组的博士生张倩等人发现，通过第三脑室注射腺病毒介导的ATF4过表述能够引起肝脏的肝细胞素抵抗，而显病态突变ATF4（dominant negative-ATF4）能够提高肝脏肝细胞理智；再进一步学术研究证实ATF4对肺脏糖代谢的抑制是通过血清素S6K1以及肝脏迷走神经信号发送至的；另外，本学术研究还证实了ATF4是之所在之处内质网表征引起肺脏肝细胞素抵抗过程之中的关键管控因子。

本学术研究揭示了之所在之处血清素ATF4在糖代谢特别的新功能，为学术研究之所在之处抑制肺脏肝细胞理智提供了一个新的前景，并拓宽了之所在之处内质网表征对肝脏肝细胞素抵抗的学术研究，非常丰富了人们对各个脑部的交互发挥作用管控糖代谢的认识，有助于加深人们对肝炎及无关的代谢病态疟疾发生前提的理解。

该项工作给予国家自然现代科学基金、科技部以及之浙江大学等现代科学学术研究基金的支持。

与血清素无关的拓展阅读：

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.