Diabetes：郭非凡等揭示下丘脑ATF4调控肝脏胰岛高雅的新功能

近日，国际学术刊物Diabetes在线发表了之前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”。该科学研究洞察了激素活化转录因子4 (ATF4) 通过激活核糖体S6K蛋白激酶(p70 S6K1)，进而抑制则有肝脏的去甲理智的分子前提，揭示了激素ATF4恒定则有代谢恒定的新功能。

2标准型肝炎是一种慢持续性代谢持续性癌症，随着生活高度的日趋提高，不能不2标准型肝炎的发病率急速减低。在此此前关于2标准型肝炎的科学研究主要集之前在肝脏等单个脑部，而各个脑部的震荡对2标准型肝炎阻碍的科学研究很少。神经，众所周知是激素，在机体则有组织的去甲理智恒定之前起非常重要的作用，近年来已逐渐带入一个科学研究热点。ATF4是CREB大家族之前的一个重要成员，此前关于ATF4转录代谢的功能科学研究主要集之前在则有组织，例如ATF4 上半身敲除激素会贫血，碳水化合物减少，能量消耗减低，去甲理智升高；成骨细胞之前特异持续性敲除ATF4也会提高去甲理智等。但是神经之前ATF4是否策划则有去甲理智的恒定尚有报道。

郭非凡科学分别独立的复旦大学张倩等人推测，通过第三脑室药剂腺病毒介导的ATF4过表达只能引来肝脏的甲状腺激素反抗，而显持续性突变ATF4（dominant negative-ATF4）只能提高肝脏去甲理智；有利于科学研究确认ATF4对则有糖代谢的恒定是通过激素S6K1以及肝脏脑干回波发送至的；另外，本科学研究还确认了ATF4是之前枢内质网应激引来则有甲状腺激素反抗过程之前的关键转录因子。

本科学研究揭示了之前枢激素ATF4在糖代谢特别的新功能，为科学研究之前枢恒定则有去甲理智给予了一个原先前景，并开辟了之前枢内质网应激对肝脏甲状腺激素反抗的科学研究，丰富了人们对各个脑部的震荡转录糖代谢的认识，适度促成人们对肝炎及相关的代谢持续性癌症发生前提的理解。

该项工作得到国家自然科学该基金会、研究之前心以及之前科院等科研成果该基金会的支持。

与激素相关的拓展阅读：

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.