Zhang Yang, Wei Qiangman, Geng Xue, Fang Guoliang
Exercise Biological Research Center, China Institute of Sport Science, Beijing 100061, China.
Metabolites. 2024 Dec 9;14(12):692. doi: 10.3390/metabo14120692.
Insulin resistance (IR) is central to the progression of non-alcoholic fatty liver disease (MAFLD). While aerobic exercise reduces hepatic fat and enhances insulin sensitivity, the specific mechanisms-particularly those involving exosomal pathways-are not fully elucidated.
Exosomes were isolated from 15 MAFLD patients' plasma following the final session of a 12-week aerobic exercise intervention. Liver fat content was measured using MRI-PDFF, and metabolic parameters were assessed via OGTT, HOMA-IR, QUICKI, and VO max. Co-culture experiments evaluated the effects of exercise-derived exosomes on IR signaling pathways. miRNA microarray analysis identified miR-324, which was quantified in high-fat diet (HFD) mice with and without exercise and compared between athletes and sedentary controls. Functional assays assessed miR-324's role in glucose and lipid metabolism, while luciferase reporter and Western blot assays confirmed ROCK1 as its direct target.
Aerobic exercise significantly reduced liver fat and improved insulin sensitivity in both MAFLD patients and HFD mice. Notably, exosomal miR-324 levels were lower in athletes than sedentary controls, indicating an inverse association with insulin sensitivity. Post-exercise, precursor and mature miR-324 increased in adipose tissue and decreased in muscle, suggesting its adipose origin and inverse regulation. Functional assays demonstrated that miR-324 modulates insulin resistance by targeting ROCK1.
Exercise-induced exosomal miR-324 from adipose tissue targets ROCK1, revealing a novel mechanism by which aerobic exercise confers hepatoprotection against insulin resistance in MAFLD. These findings enhance our understanding of how exercise influences metabolic health and may inform future therapeutic strategies for managing MAFLD and related conditions.
胰岛素抵抗（IR）是非酒精性脂肪性肝病（MAFLD）进展的核心因素。虽然有氧运动可减少肝脏脂肪并增强胰岛素敏感性，但其具体机制，尤其是涉及外泌体途径的机制尚未完全阐明。
在一项为期12周的有氧运动干预的最后阶段后，从15名MAFLD患者的血浆中分离出外泌体。使用磁共振成像-质子密度脂肪分数（MRI-PDFF）测量肝脏脂肪含量，并通过口服葡萄糖耐量试验（OGTT）、稳态模型评估胰岛素抵抗（HOMA-IR）、定量胰岛素敏感性检查指数（QUICKI）和最大摄氧量（VO max）评估代谢参数。共培养实验评估运动来源的外泌体对IR信号通路的影响。miRNA微阵列分析鉴定出miR-324，在高脂饮食（HFD）小鼠中对其进行定量，比较运动组和不运动组，并在运动员和久坐不动的对照组之间进行比较。功能测定评估miR-324在葡萄糖和脂质代谢中的作用，而荧光素酶报告基因和蛋白质印迹分析证实ROCK1是其直接靶点。
有氧运动显著降低了MAFLD患者和HFD小鼠的肝脏脂肪并改善了胰岛素敏感性。值得注意的是，运动员中外泌体miR-324水平低于久坐不动的对照组，表明其与胰岛素敏感性呈负相关。运动后，脂肪组织中前体和成熟miR-324增加，肌肉中减少，表明其来源于脂肪组织且存在反向调节。功能测定表明miR-324通过靶向ROCK1调节胰岛素抵抗。
运动诱导的脂肪组织来源的外泌体miR-324靶向ROCK1，揭示了有氧运动对MAFLD中胰岛素抵抗具有肝脏保护作用的新机制。这些发现加深了我们对运动如何影响代谢健康的理解，并可能为未来管理MAFLD及相关病症的治疗策略提供参考。
