Diabetes：下丘脑调控肝胰岛素抵抗机制揭示

　　中科院上海生命科学研究院营养科学研究所郭非凡研究组新近发现下丘脑调控肝脏胰岛素敏感性的新机制，研究论文日前在线发表在国际学术刊物《糖尿病》杂志上。

　　下丘脑活化转录因子4（ATF4）是神经元内部含有的“反应结合蛋白”物质（CREB）家族中的一个重要成员，科研人员发现，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能够提高肝脏胰岛素敏感性。科研人员进一步研究证实，ATF4对外周糖代谢的调节是通过下丘脑激活核糖体（S6K1）以及肝脏迷走神经信号传递的。另外，科研人员还证实了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。

　　专家认为，该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代谢性疾病发生机制的理解。

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Central activating transcription factor (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve
Abstract
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.