Diabetes：郭非凡等揭示下丘脑ATF4调控肝脏胰岛特质的新功能

昨日，国际刊物Diabetes在线发表了之前科院武汉生科院营养科学研究工作所郭非凡组的研究工作论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该研究工作阐释了神经递质活化核糖体因子4 (ATF4) 通过激活核糖体S6K蛋白激酶(p70 S6K1)，进而抑制向外脾脏的胰岛真挚的分子系统，阐释了神经递质ATF4抑制向外代谢数学模型的新系统。

2型乳癌是一种慢性代谢性疾病，随着生活水平的越来越提高，我国2型乳癌的患病率急速增加。目前关于2型乳癌的研究工作主要集之前在脾脏等单个器官，而各个器官的交互作用对2型乳癌影响的研究工作大多。之前枢神经系统，尤其是神经递质，在机体向外民间组织的胰岛真挚抑制之前起非常重要的作用，近年来已逐渐成为一个研究工作热点。ATF4是CREB家族之前的一个重要成员，之前关于ATF4抑制代谢的系统研究工作主要集之前在向外民间组织，例如ATF4 全身敲除豚鼠时会贫血，饲料减少，能量消耗增加，胰岛真挚增大；成骨细胞之前特异性敲除ATF4也时会提高胰岛真挚等。但是之前枢神经系统之前ATF4究竟参与向外胰岛真挚的抑制尚待报道。

郭非凡分别独立的科研人员张倩等人发现，通过第三脑室注射腺病毒诱导的ATF4过表达出来能够引发脾脏的胰岛素对抗，而显性甲基化ATF4（dominant negative-ATF4）能够提高脾脏胰岛真挚；进一步研究工作得出结论ATF4对向外糖代谢的抑制是通过神经递质S6K1以及脾脏迷走神经回波引导的；另外，本研究工作还得出结论了ATF4是之前枢肝细胞诱发引发向外胰岛素对抗过程之前的关键性抑制因子。

本研究工作阐释了之前枢神经递质ATF4在糖代谢方面的新系统，为研究工作之前枢抑制向外胰岛真挚提供了一个新前途，并改建了之前枢肝细胞诱发对脾脏胰岛素对抗的研究工作，丰富了人们对各个器官的交互作用抑制糖代谢的认识，更进一步加深人们对乳癌及具体的代谢性疾病暴发系统的理解。

该项工作受益国家自然科学基金、科技部以及之前科院等科研基金的支持。

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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.