Li Nan, Zhang Liang, Guo Qiaofeng, Yang Xiaoying, Liu Changjiang, Zhou Yue
Center for Physical Education, Xi'an Jiaotong University, Xi'an 710049, China.
Department of Exercise Physiology, Beijing Sport University, Beijing 100084, China.
Metabolites. 2025 Aug 27;15(9):572. doi: 10.3390/metabo15090572.
Insulin resistance (IR) is a complex and multifactorial disorder that contributes to type 2 diabetes and cardiovascular disease. MicroRNAs (miRNAs) play important roles in diverse developmental and disease processes. However, the molecular mechanisms of IR are unclear. This paper aims to explore the role of miRNA in regulating IR and to elucidate the mechanisms responsible for these effects. IR models were created by feeding a high-fat diet (HFD) to mice or stimulating 3T3-L1 cells with palmitate. Twelve weeks of HFD trigger weight gain, leading to lipid accumulation and insulin resistance in mice. The expression profiles of miRNAs in adipose tissues (AT) from the HFD-induced mouse models were analyzed. The relationship between miR-221-3p and SOCS1 was determined using dual luciferase reporter gene assays. Metabolic alterations in AT were investigated by real-time PCR and Western blot. miR-221-3p was significantly increased in AT. HFD-induced disturbances in glucose homeostasis were aggravated by miR-221-3p upregulation. The inhibition of miR-221-3p promoted insulin sensitivity including reduced lipid accumulation and the disruption of glucose metabolism. Of note, the 3'-UTR of SOCS1 was found to be a direct target of miR-221-3p. The SOCS1 inhibitor attenuated miR-221-3p-induced increases in IRS-1 phosphorylation, AKT phosphorylation, and GLUT4. miR-221-3p was considered to be involved in the PI3K/AKT signaling pathway, thus leading to increased insulin sensitivity and decreased IR in HFD-fed mice and 3T3-L1 adipocytes. The miR-221-3p/SOCS1 axis in AT plays a pivotal role in the regulation of glucose metabolism, providing a novel target for treating IR and diabetes.
胰岛素抵抗（IR）是一种复杂的多因素疾病，与2型糖尿病和心血管疾病的发生有关。微小RNA（miRNA）在多种发育和疾病过程中发挥着重要作用。然而，IR的分子机制尚不清楚。本文旨在探讨miRNA在调节IR中的作用，并阐明其作用机制。通过给小鼠喂食高脂饮食（HFD）或用棕榈酸刺激3T3-L1细胞建立IR模型。12周的HFD喂养导致小鼠体重增加，引发脂质蓄积和胰岛素抵抗。分析了HFD诱导的小鼠模型脂肪组织（AT）中miRNA的表达谱。采用双荧光素酶报告基因检测法确定miR-221-3p与SOCS1之间的关系。通过实时定量PCR和蛋白质免疫印迹法研究AT中的代谢变化。miR-221-3p在AT中显著上调。miR-221-3p的上调加剧了HFD诱导的葡萄糖稳态紊乱。抑制miR-221-3p可促进胰岛素敏感性，包括减少脂质蓄积和改善葡萄糖代谢紊乱。值得注意的是，发现SOCS1的3'-非翻译区（3'-UTR）是miR-221-3p的直接靶标。SOCS1抑制剂可减弱miR-221-3p诱导的胰岛素受体底物1（IRS-1）磷酸化、蛋白激酶B（AKT）磷酸化和葡萄糖转运蛋白4（GLUT4）增加。miR-221-3p被认为参与了磷脂酰肌醇-3激酶（PI3K）/AKT信号通路，从而导致HFD喂养的小鼠和3T3-L1脂肪细胞中胰岛素敏感性增加和IR降低。AT中的miR-221-3p/SOCS1轴在葡萄糖代谢调节中起关键作用，为治疗IR和糖尿病提供了新的靶点。
