miR-182 Regulates Metabolic Homeostasis by Modulating Glucose Utilization in Muscle
miR-182 Regulates Metabolic Homeostasis by Modulating Glucose Utilization in Muscle
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miR-182 通过调节肌肉中的葡萄糖利用来调节代谢稳态
DOI：
10.1016/j.celrep.2016.06.040
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发表时间：
2016
期刊：
影响因子：
8.8
通讯作者：
Ying H
中科院分区：
文献类型：
--
作者：
Zhang Duo;Li Yan;Yao Xuan;Wang Hui;Zhao Lei;Jiang Haowen;Yao Xiaohan;Zhang Shengjie;Ye Cheng;Liu Wei;Cao Hongchao;Yu Shuxian;Wang Yu-cheng;Li Qiong;Jiang Jingjing;Liu Yi;Zhang Ling;Liu Yun;Iwai Naoharu;Wang Hui;Li Jingya;Li Jia;Li Xihua;Jin Zi-Bing;Ying H
了解骨骼肌中的纤维类型规格和代谢开关可以深入了解生理学和疾病中的能量代谢。在这里，我们发现 miR-182 在快肌中高表达，并且与血糖水平负相关。 miR-182 敲除小鼠表现出肌肉损失、快到慢的纤维类型转换以及葡萄糖代谢受损。机制研究表明，miR-182 通过靶向 FoxO1 和 PDK4 来调节肌肉中的葡萄糖利用，而 FoxO1 和 PDK4 通过丙酮酸脱氢酶复合物 (PDHC) 控制燃料选择。短期高脂饮食 (HFD) 喂养会通过肿瘤坏死因子 α (TNFα) 降低肌肉 miR-182 水平，从而导致 FoxO1/PDK4 上调。在 HFD 喂养的小鼠中恢复 miR-182 表达可诱导更快的肌肉表型，降低肌肉 FoxO1/PDK4 水平，并改善葡萄糖代谢。我们的工作共同将 miR-182 确立为一个关键的调节因子，可以对燃料使用和葡萄糖稳态进行强大而精确的控制。我们的研究表明，代谢向更快、更多糖酵解表型的转变有利于血糖控制。
Understanding the fiber-type specification and metabolic switch in skeletal muscle provides insights into energy metabolism in physiology and diseases. Here, we show that miR-182 is highly expressed in fast-twitch muscle and negatively correlates with blood glucose level. miR-182 knockout mice display muscle loss, fast-to-slow fiber-type switching, and impaired glucose metabolism. Mechanistic studies reveal that miR-182 modulates glucose utilization in muscle by targeting FoxO1 and PDK4, which control fuel selection via the pyruvate dehydrogenase complex (PDHC). Short-term high-fat diet (HFD) feeding reduces muscle miR-182 levels by tumor necrosis factor α (TNFα), which contributes to the upregulation of FoxO1/PDK4. Restoration of miR-182 expression in HFD-fed mice induces a faster muscle phenotype, decreases muscle FoxO1/PDK4 levels, and improves glucose metabolism. Together, our work establishes miR-182 as a critical regulator that confers robust and precise controls on fuel usage and glucose homeostasis. Our study suggests that a metabolic shift toward a faster and more glycolytic phenotype is beneficial for glucose control.