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，国际季刊Diabetes在线刊出了中都科院天津生科院营养科学研究课题所郑非凡第三组的研究课题文章“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该研究课题阐明了皮质活化RNA变异4 (ATF4) 通过激活蛋白质S6K蛋白激酶(p70 S6K1)，进而抑制骨骼肌脾脏的胰脏感开放性的分子前提，揭示了皮质ATF4恒定骨骼肌细胞内稳态的新功能。

2型号白血病是一种慢开放性细胞内开放性疾病，随着生活水平的逐渐提高，不能不2型号白血病的发病率急速减少。目前关于2型号白血病的研究课题主要密集在脾脏等单个器官，而各个器官的交互起到对2型号白血病影响的研究课题很少。帝都神经系统，尤其是皮质，在机体骨骼肌其第三组织的胰脏感开放性恒定中都起非常最主要的起到，国际上已逐渐成为一个研究课题热点。ATF4是CREB家族中都的一个最主要全体成员，在此之前关于ATF4介导细胞内的功能研究课题主要密集在骨骼肌其第三组织，例如ATF4 全身敲除小鼠会病症，饲料减低，能量消耗减少，胰脏感开放性增大；成骨细胞中都特异开放性敲除ATF4也会提高胰脏感开放性等。但是帝都神经系统中都ATF4是否参与骨骼肌胰脏感开放性的恒定尚无刊文。

郑非凡研究课题第三组的科研人员张倩等人发现，通过第三脑室麻醉腺病毒介导的ATF4过表达只能引起脾脏的血清顽抗，而显开放性突变ATF4（dominant negative-ATF4）只能提高脾脏胰脏感开放性；再进一步研究课题确认ATF4对骨骼肌糖细胞内的恒定是通过皮质S6K1以及脾脏消化道接收机发送至的；另外，本研究课题还确认了ATF4是帝都细胞内神经细胞引起骨骼肌血清顽抗过程中都的关键因素介导变异。

本研究课题揭示了帝都皮质ATF4在糖细胞内方面的新功能，为研究课题帝都恒定骨骼肌胰脏感开放性提供了一个在此之后前景，并拓宽了帝都细胞内神经细胞对脾脏血清顽抗的研究课题，丰富了人们对各个器官的交互起到介导糖细胞内的认识，最大限度加深人们对白血病及无关的细胞内开放性疾病发生前提的理解。

该项工作想得到国家自然科学私人机构、科技部以及中都科院等科研私人机构的赞同。

与皮质无关的拓展阅读：

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.