Chongqing Key Lab of Medicinal Chemistry & Molecular Pharmacology of Technology, Chongqing University of Technology, Chongqing 400054, China.
Acta Biochim Biophys Sin (Shanghai). 2021 Feb 4;53(2):160-169. doi: 10.1093/abbs/gmaa157.
Thioredoxin-interacting protein (Txnip) has emerged as a key regulator of insulin resistance. In this study, we investigated the roles of geniposide and Txnip in insulin resistance in differentiated 3T3-L1 adipocytes. Our results revealed that geniposide markedly enhanced glucose uptake, increased the protein levels of insulin receptor substrate (IRS)-1 and GLUT-1, and prevented the phosphorylation of IRS-1 and Akt Thr308 induced by insulin resistance in 3T3-L1 adipocytes. We also observed that geniposide accelerated protein degradation of Txnip through proteasome pathway, and knockdown of Txnip with small interfering RNA attenuated the effect of geniposide on insulin signaling molecules, implying that Txnip played a pivotal role in the regulation of insulin signaling molecules by geniposide in 3T3-L1 adipocytes. Furthermore, geniposide induced the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) in the presence of high glucose in differentiated 3T3-L1 adipocytes, while compound C, an inhibitor of AMPK, prevented the effect of geniposide on Txnip degradation and the regulation of glucose uptake and insulin signaling molecules including p-IRS-1, IRS-1, and GLUT-1 in differentiated 3T3-L1 adipocytes. Taken together, all these findings suggest that geniposide improves the insulin signaling defect possibly by AMPK-mediated Txnip degradation in 3T3-L1 adipocytes.
硫氧还蛋白相互作用蛋白（Txnip）已成为胰岛素抵抗的关键调节因子。在本研究中，我们研究了京尼平苷和 Txnip 在分化的 3T3-L1 脂肪细胞中胰岛素抵抗中的作用。结果表明，京尼平苷显著增强葡萄糖摄取，增加胰岛素受体底物（IRS）-1 和 GLUT-1 的蛋白水平，并防止胰岛素抵抗诱导的 IRS-1 和 Akt Thr308 的磷酸化。我们还观察到京尼平苷通过蛋白酶体途径加速 Txnip 的蛋白降解，并用小干扰 RNA 敲低 Txnip 减弱了京尼平苷对胰岛素信号分子的作用，表明 Txnip 在京尼平苷调节 3T3-L1 脂肪细胞胰岛素信号分子中起关键作用。此外，京尼平苷在分化的 3T3-L1 脂肪细胞中高葡萄糖存在下诱导单磷酸腺苷激活蛋白激酶（AMPK）的磷酸化，而 AMPK 的抑制剂 Compound C 可阻止京尼平苷对 Txnip 降解以及对葡萄糖摄取和胰岛素信号分子（包括 p-IRS-1、IRS-1 和 GLUT-1）的调节作用。综上所述，这些发现表明京尼平苷通过 AMPK 介导的 3T3-L1 脂肪细胞中 Txnip 降解改善胰岛素信号缺陷。
