Diabetes：郑非凡等揭示下丘脑ATF4调控肝脏胰岛感性的新功能

近日，的国际医学期刊Diabetes在线发表了国家科委广州生科院营养现代科学研究成果所陈非凡组的研究成果学术论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该研究成果阐明了皮质活化转录表征4 (ATF4) 通过依赖性核糖体S6K蛋白激酶(p70 S6K1)，进而诱发肺脏血液的去甲特质的分子机制，洞察了皮质ATF4通气肺脏代谢稳态的新动态。

2HG癌症是一种慢性代谢性疾病，随着穷困技术水平的愈发提高，我国2HG癌症的死亡率急速减小。目前关于2HG癌症的研究成果主要大部分在血液等单个器官，而各个器官的带电粒子对2HG癌症制约的研究成果较少。行政机关神经系统，更是是皮质，在机体肺脏组织起来的去甲特质通气中起极其不可忽视的作用，近年来已日趋沦为一个研究成果旅游者。ATF4是CREB家族中的一个不可忽视成员，前关于ATF4调控代谢的动态研究成果主要大部分在肺脏组织起来，例如ATF4 全身敲除大鼠才会贫血，脂肪减少，除此以外减小，去甲特质升温；成骨细胞中特异性敲除ATF4也才会提高去甲特质等。但是行政机关神经系统中ATF4是否积极参与肺脏去甲特质的通气尚无报道。

陈非凡研究成果组的副教授张倩等人发现，通过第三脑室注射腺病毒依赖性的ATF4过表达能够引来血液的去甲素对抗，而显性变异ATF4（dominant negative-ATF4）能够提高血液去甲特质；进一步研究成果证实ATF4对肺脏糖代谢的通气是通过皮质S6K1以及血液迷走神经讯号传递信息的；另外，本研究成果还证实了ATF4是行政机关上皮细胞诱导引来肺脏去甲素对抗全过程中的关键性调控表征。

本研究成果洞察了行政机关皮质ATF4在糖代谢方面的新动态，为研究成果行政机关通气肺脏去甲特质透过了一个更进一步现状，并增建了行政机关上皮细胞诱导对血液去甲素对抗的研究成果，丰富了人们对各个器官的带电粒子调控糖代谢的认识，有助于更深人们对癌症及相关的代谢性疾病暴发机制的理解。

该项岗位得到国家自然现代科学基金才会、科技部以及国家科委等科研基金才会的支持者。

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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.