Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden.
Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.
Mol Biol Cell. 2023 Nov 1;34(12):ar124. doi: 10.1091/mbc.E23-03-0078. Epub 2023 Sep 13.
Adipocyte dysfunction is a crucial driver of insulin resistance and type 2 diabetes. We identified EH domain-containing protein 2 (EHD2) as one of the most highly upregulated genes at the early stage of adipose-tissue expansion. EHD2 is a dynamin-related ATPase influencing several cellular processes, including membrane recycling, caveolae dynamics, and lipid metabolism. Here, we investigated the role of EHD2 in adipocyte insulin signaling and glucose transport. Using C57BL6/N EHD2 knockout mice under short-term high-fat diet conditions and 3T3-L1 adipocytes we demonstrate that EHD2 deficiency is associated with deterioration of insulin signal transduction and impaired insulin-stimulated GLUT4 translocation. Furthermore, we show that lack of EHD2 is linked with altered plasma membrane lipid and protein composition, reduced insulin receptor expression, and diminished insulin-dependent SNARE protein complex formation. In conclusion, these data highlight the importance of EHD2 for the integrity of the plasma membrane milieu, insulin receptor stability, and downstream insulin receptor signaling events, involved in glucose uptake and ultimately underscore its role in insulin resistance and obesity.
脂肪细胞功能障碍是胰岛素抵抗和 2 型糖尿病的关键驱动因素。我们发现 EH 结构域蛋白 2（EHD2）是脂肪组织扩张早期上调最明显的基因之一。EHD2 是一种与动力蛋白相关的 ATP 酶，影响包括膜回收、质膜窖动态和脂质代谢在内的多种细胞过程。在这里，我们研究了 EHD2 在脂肪细胞胰岛素信号和葡萄糖转运中的作用。使用 C57BL6/N EHD2 敲除小鼠在短期高脂肪饮食条件下和 3T3-L1 脂肪细胞中，我们证明 EHD2 缺乏与胰岛素信号转导恶化和胰岛素刺激的 GLUT4 易位受损有关。此外，我们还表明，缺乏 EHD2 与质膜脂质和蛋白质组成改变、胰岛素受体表达减少以及胰岛素依赖性 SNARE 蛋白复合物形成减少有关。总之，这些数据强调了 EHD2 对于质膜环境、胰岛素受体稳定性以及涉及葡萄糖摄取的下游胰岛素受体信号事件完整性的重要性，并最终强调了其在胰岛素抵抗和肥胖中的作用。
