Diabetes：郭非凡等探究下丘脑ATF4调控肝脏胰岛感性的新功能

已对，国际间学术博士论文Diabetes在线发表了工程技术南京生科院营养科学研究课题所杨非凡组成员的研究课题博士论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该研究课题说明了中枢神经系统活化转录生物体4 (ATF4) 通过内源性蛋白质S6K蛋白激酶(p70 S6K1)，进而抑制肺脏脾脏的家兔真挚的分子可程序，概述了中枢神经系统ATF4调控肺脏细胞内一个系统的补丁。

2型号癌症是一种慢性细胞内性疾病，随着日常生活水平的越发提高，我国2型号癌症的发病率急速减小。在此之前关于2型号癌症的研究课题主要以外在脾脏等单个生殖器官，而各个生殖器官的化学键对2型号癌症影响的研究课题很少。中枢神经系统，尤其是中枢神经系统，在机体肺脏组成员织的家兔真挚调控中起非常极其重要的作用，近十年已逐渐成为一个研究课题热点。ATF4是CREB家族中的一个极其重要成员，之前关于ATF4调控细胞内的动态研究课题主要以外在肺脏组成员织，例如ATF4 身体敲除豚鼠会疾病，脂肪减低，能量消耗减小，家兔真挚升高；成骨细胞中特异性敲除ATF4也会提高家兔真挚等。但是中枢神经系统中ATF4是否是参与肺脏家兔真挚的调控尚无报道。

杨非凡研究课题组成员的博士生张倩等人见到，通过第三肺部注射腺病毒内源性的ATF4过表达能够造成了脾脏的家兔素抗击，而显性突变ATF4（dominant negative-ATF4）能够提高脾脏家兔真挚；进一步研究课题确认ATF4对肺脏糖细胞内的调控是通过中枢神经系统S6K1以及脾脏迷走神经信号传递的；另外，本研究课题还确认了ATF4是中枢内质网应激造成了肺脏家兔素抗击过程中的关键调控生物体。

本研究课题概述了中枢中枢神经系统ATF4在糖细胞内方面的补丁，为研究课题中枢调控肺脏家兔真挚提供了一个新的前景，并开辟了中枢内质网应激对脾脏家兔素抗击的研究课题，丰富了人们对各个生殖器官的化学键调控糖细胞内的认识，有助于加深人们对癌症及相关的细胞内性疾病发生程序的理解。

该项指导工作得到国家自然科学基金、经济部以及工程技术等科研基金的支持。

与中枢神经系统相关的开拓朗读：

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.