Obesity is associated with an increased risk of developing insulin resistance (IR) and type 2 diabetes (T2D). A diverse group of factors including miRNA has been implicated in the pathogenesis of these two metabolic conditions, although underlying molecular mechanisms involved are not well defined. Here, we provide evidence that hepatic miR-125a levels are diminished in both genetic as well as dietary mouse models of obesity. Overexpression of miR-125a enhanced insulin signaling and attenuated cellular lipid accumulation in HepG2 cells and Hepa1-6 cells. Likewise, treatment of mice with ago-miR-125a increased insulin sensitivity, similar to overexpression of miR-125a, whereas treatment of mice with antago-miR-125a blunted the insulin sensitivity. Furthermore, overexpression of miR-125a in mice previously fed a high-fat diet (HFD), significantly improved insulin sensitivity, and attenuated obesity-linked hepatic steatosis and hepatocyte lipid accumulation. In addition, we show that ELOVL fatty acid elongase 6 (Elovl6) is a direct target of miR-125a, and participates in miR-125a mediated regulation of insulin sensitivity and lipid metabolism. These data led us to conclude that dysregulated miR-125a expression augments the development of obesity-induced IR and that miR-125a might serve as a therapeutic target for the development of new drug(s) in the clinical management of metabolic diseases.

中文翻译：

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microRNA-125a的失调会导致肥胖相关的胰岛素抵抗，并导致小鼠脂质代谢失调。

肥胖与发展胰岛素抵抗（IR）和2型糖尿病（T2D）的风险增加有关。尽管涉及的潜在分子机制尚未明确，但包括miRNA在内的多种因素也参与了这两种代谢疾病的发病机理。在这里，我们提供证据表明，肥胖的遗传模型和饮食模型中的肝脏miR-125a水平均降低。miR-125a的过表达增强了HepG2细胞和Hepa1-6细胞中的胰岛素信号传导并减弱了细胞脂质的蓄积。同样，用miR-125a以前的小鼠治疗会增加胰岛素敏感性，类似于miR-125a的过表达，而用antago-miR-125a的小鼠治疗会使胰岛素敏感性减弱。此外，miR-125a在先前饲喂高脂饮食（HFD）的小鼠中过表达，显着改善胰岛素敏感性，并减轻肥胖相关的肝脂肪变性和肝细胞脂质蓄积。此外，我们显示ELOVL脂肪酸延伸酶6（Elovl6）是miR-125a的直接靶标，并参与miR-125a介导的胰岛素敏感性和脂质代谢的调节。这些数据使我们得出结论，miR-125a表达失调会促进肥胖诱导的IR的发展，miR-125a可能在代谢性疾病的临床管理中作为新药开发的治疗目标。并参与miR-125a介导的胰岛素敏感性和脂质代谢的调节。这些数据使我们得出结论，miR-125a表达失调会促进肥胖诱导的IR的发展，miR-125a可能在代谢性疾病的临床管理中作为新药开发的治疗目标。并参与miR-125a介导的胰岛素敏感性和脂质代谢的调节。这些数据使我们得出结论，miR-125a表达失调会促进肥胖诱导的IR的发展，miR-125a可能在代谢性疾病的临床管理中作为新药开发的治疗目标。