Diabetes：郭非凡等揭示下丘脑ATF4调控肝脏胰岛素敏感性的新功能

近日，国际学术期刊Diabetes在线发表了中科院上海生科院营养科学研究所郭非凡组的研究论文“Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve”。该研究阐明了下丘脑活化转录因子4 (ATF4) 通过激活核糖体S6K蛋白激酶(p70 S6K1)，进而抑制外周肝脏的胰岛素敏感性的分子机制，揭示了下丘脑ATF4调节外周代谢稳态的新功能。

2型糖尿病是一种慢性代谢性疾病，随着生活水平的日益提高，我国2型糖尿病的发病率急速增加。目前关于2型糖尿病的研究主要集中在肝脏等单个器官，而各个器官的交互作用对2型糖尿病影响的研究很少。中枢神经系统，尤其是下丘脑，在机体外周组织的胰岛素敏感性调节中起非常重要的作用，近年来已逐渐成为一个研究热点。ATF4是CREB家族中的一个重要成员，之前关于ATF4调控代谢的功能研究主要集中在外周组织，例如ATF4 全身敲除小鼠会贫血，脂肪减少，能量消耗增加，胰岛素敏感性升高；成骨细胞中特异性敲除ATF4也会提高胰岛素敏感性等。但是中枢神经系统中ATF4是否参与外周胰岛素敏感性的调节尚无报道。

郭非凡研究组的博士生张倩等人发现，通过第三脑室注射腺病毒介导的ATF4过表达能够引起肝脏的胰岛素抵抗，而显性突变ATF4（dominant negative-ATF4）能够提高肝脏胰岛素敏感性；进一步研究证实ATF4对外周糖代谢的调节是通过下丘脑S6K1以及肝脏迷走神经信号传递的；另外，本研究还证实了ATF4是中枢内质网应激引起外周胰岛素抵抗过程中的关键调控因子。

本研究揭示了中枢下丘脑ATF4在糖代谢方面的新功能，为研究中枢调节外周胰岛素敏感性提供了一个新的前景，并拓宽了中枢内质网应激对肝脏胰岛素抵抗的研究，丰富了人们对各个器官的交互作用调控糖代谢的认识，有助于加深人们对糖尿病及相关的代谢性疾病发生机制的理解。

该项工作得到国家自然科学基金、科技部以及中科院等科研基金的支持。

与下丘脑相关的拓展阅读：

• NEJM：下丘脑刺激有助于改善早期帕金森症状
• PNAS：瘦素（leptin)可能治疗下丘脑性闭经

doi:10.2337/db12-1050
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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 have 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 intraventricular (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.