Diabetes：郭非凡等揭示下丘脑ATF4调控肝脏胰岛坦率的新功能

近来，国际学术期刊Diabetes在线发表了中都科院上海生科院营养科学研究研究所姚非凡组的研究期刊“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该研究阐明了皮质活化转录因子4 (ATF4) 通过激活核糖体S6K蛋白激酶(p70 S6K1)，进而诱导肺脏肝的去甲知性的分子可机制，探究了皮质ATF4适度肺脏葡萄糖稳态的补丁。

2改型乳癌是一种慢性葡萄糖性疾病，随着社会生活水平的逐渐降低，中华民族2改型乳癌的发病率急速减少。目前关于2改型乳癌的研究主要临近都在肝等单个器官，而各个器官的交互效用对2改型乳癌影响的研究并不多。中都枢神经系统，尤其是皮质，在机体肺脏民间组织的去甲知性适度中都起非常重要的效用，近些年来已慢慢地成为一个研究热点。ATF4是CREB家族中都的一个重要成员，前关于ATF4催化反应葡萄糖的功能研究主要临近都在肺脏民间组织，例如ATF4 全身敲除人体内亦会贫血，脂肪减少，能量消耗减少，去甲知性升高；成骨细胞中都特异性敲除ATF4也亦会降低去甲知性等。但是中都枢神经系统中都ATF4是否参与肺脏去甲知性的适度尚未有报道。

姚非凡研究小组的副所长张倩等人发现，通过第三脑室注射腺病毒介导的ATF4过强调只能引起肝的去甲素抵抗，而显性突变ATF4（dominant negative-ATF4）只能降低肝去甲知性；有利于研究得出结论ATF4对肺脏糖葡萄糖的适度是通过皮质S6K1以及肝迷走神经信号发送至的；另外，本研究还得出结论了ATF4是中都枢内质网应激引起肺脏去甲素抵抗过程中都的关键催化反应因子。

本研究探究了中都枢皮质ATF4在糖葡萄糖方面的补丁，为研究中都枢适度肺脏去甲知性缺少了一个新的前景，并拓宽了中都枢内质网应激对肝去甲素抵抗的研究，丰富了人们对各个器官的交互效用催化反应糖葡萄糖的认识，并能缓和人们对乳癌及关的的葡萄糖性疾病起因机制的理解。

该项岗位得到国家自然科学研究基金、科技部以及中都科院等科研基金的支持。

与皮质关的的扩张阅读：

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.