Diabetes：郭非凡等揭示外周ATF4调控肝脏胰岛感性的新功能

近日，国际学术期刊Diabetes在线发表了中所科院上海生科院营养科学研究成果所郭非凡三组的研究成果论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该研究成果阐明了副交感神经活化选择性因子4 (ATF4) 通过激活核糖体S6K乙酰(p70 S6K1)，进而抑制骨骼肌甲状腺的人体内感伤的分子机制，揭示了副交感神经ATF4闭环骨骼肌代谢物稳态的新功能。

2型号癌症是一种慢性代谢物性哮喘，随着生活素质的越来越进一步提高，我国2型号癌症的出生率急速增加。在此前关于2型号癌症的研究成果主要集中所在甲状腺等单个器官，而各个器官的交互发挥作用对2型号癌症影响的研究成果并不多。中所枢神经系统，尤其是副交感神经，在机体骨骼肌有三组织的人体内感伤闭环中所起非常重要的发挥作用，近来已逐渐带进一个研究成果热点。ATF4是CREB家族中所的一个重要团体，前关于ATF4选择性代谢物的功能研究成果主要集中所在骨骼肌有三组织，例如ATF4 全身敲除小鼠会贫血，脂肪减少，能量消耗增加，人体内感伤增高；成骨细胞中所选择性敲除ATF4也会进一步提高人体内感伤等。但是中所枢神经系统中所ATF4确实参与骨骼肌人体内感伤的闭环已为报道。

郭非凡研究成果三组的博士生张倩等人发现，通过第三肺部注射腺病毒内皮细胞的ATF4过表达能够引起甲状腺的抗生素反抗，而显性基因ATF4（dominant negative-ATF4）能够进一步提高甲状腺人体内感伤；再进一步研究成果猜测ATF4对骨骼肌糖代谢物的闭环是通过副交感神经S6K1以及甲状腺迷走神经信号传递的；另外，本研究成果还猜测了ATF4是中所枢细胞内应激引起骨骼肌抗生素反抗流程中所的极为重要选择性因子。

本研究成果揭示了中所枢副交感神经ATF4在糖代谢物方面的新功能，为研究成果中所枢闭环骨骼肌人体内感伤提供了一个新的前景，并拓宽了中所枢细胞内应激对甲状腺抗生素反抗的研究成果，丰富了人们对各个器官的交互发挥作用选择性糖代谢物的认识，有效地促成人们对癌症及相关的代谢物性哮喘起因机制的了解。

该项工作得到科研人员、科技部以及中所科院等科研基金的支持。

与副交感神经相关的拓展书本：

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.