Down-regulation of MicroRNA-592 in obesity contributes to hyperglycemia and insulin resistance
Down-regulation of MicroRNA-592 in obesity contributes to hyperglycemia and insulin resistance
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肥胖中 MicroRNA-592 的下调导致高血糖和胰岛素抵抗
DOI：
10.1016/j.ebiom.2019.03.041
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发表时间：
2019-04-01
期刊：
影响因子：
11.1
通讯作者：
Li, Yao
中科院分区：
文献类型：
--
作者：
Song, Yuping;Wu, Ling;Li, Yao
背景：许多研究表明，microRNAs是一类小的、非编码的RNA分子，在调节糖脂平衡方面发挥着重要作用。本研究旨在探讨miR-592在肥胖相关代谢紊乱中的作用，包括高血糖和胰岛素抵抗。方法：采用定量逆转录聚合酶链式反应检测miR-592在肥胖小鼠和人类肝脏中的表达水平。利用锁定核酸和腺病毒分别在瘦小鼠和肥胖小鼠体内进行功能丧失和功能获得实验，探讨miR-592的代谢功能。通过Western blotting和荧光素酶报告分析确定miR-592的分子靶点。结果：我们发现miR-592在肥胖小鼠和人的肝脏中的表达显著降低。抑制miR-592导致瘦小鼠血糖水平升高，糖异生增强，胰岛素敏感性降低。相反，腺病毒介导的肝脏miR-592过表达改善了肥胖小鼠的代谢紊乱。从机制上讲，我们发现转录因子Forkhead box O1(FOXO1)是miR-592调节其代谢功能的直接靶基因。MIR-592通过与FOXO1的3‘非翻译区结合，抑制FOXO1的mRNA和蛋白表达。说明：我们的研究结果表明，肥胖相关的miR-592下调在代谢性疾病的进展中起着重要作用。肝脏miR-592的修复可改善肥胖小鼠的糖脂代谢。(C)《2019年》，爱思唯尔出版。
Background: Many studies have demonstrated that microRNAs, a class of small and non-coding RNA molecules, play an important role in the regulation of glucose and lipid homeostasis. In the present study, we sought to investigate the function of miR-592 in the development of obesity-associated metabolic disorders, including hyperglycemia andinsulin resistance.Methods: The expression levels ofmiR-592 were measured in the liver of obese mice and humans by quantitative reverse transcription PCR. Loss-and gain-of function experiments were employed to explore the metabolic function of miR-592 using locked nucleic acids and adenovirus in lean and obese mice, respectively. The molecular target of miR-592 was determined by western blotting and luciferase reporter assays.Findings: We found a significant decreased expression of miR-592 in the liver of obese mice and humans. Inhibition of miR-592 led to elevated blood glucose levels, enhanced gluconeogenesis and reduced insulin sensitivity in lean mice. In contrast, adenovirus-mediated overexpression of hepatic miR-592 improved metabolic disorders in obese mice. Mechanistically, we found that the transcription factor forkhead box O1 (FOXO1) is a direct target gene of miR-592 to mediate its metabolic functions. miR-592 was able to inhibit the mRNA and protein expression of FOXO1 by binding to its 3'-untranslated region.Interpretations: Our findings demonstrate that obesity-associated down-regulation of miR-592 plays an important role in the progression of metabolic diseases. Restoration of hepatic miR-592 could improve glucose and lipid metabolism in obese mice. (C) 2019 Published by Elsevier B.V.