Quercetin and EGCG exhibit anti-diabetic and anti-obesity activities, however, their interactive effects in anti-diabetic/anti-obesity actions and underlying mechanisms remain unclear. This study aimed to fill these knowledge gaps. Quercetin, EGCG or their combination attenuated insulin resistance and decreased hepatic gluconeogenesis in high-fat-high-fructose diet (HFFD)-fed C57BL/6 mice and in palmitic acid (PA)-treated HepG2 cells. In mice, supplementation with quercetin (0.05%w/w), EGCG (0.05%w/w) and their combination (quercetin 0.05%+EGCG 0.05%w/w) reduced weight gain and fasting blood glucose and improved serum biochemical parameters. Compare with quercetin/EGCG alone, the quercetin-EGCG combination reduced gluconeogenesis to a greater extent via IRS-1/Akt/FOXO1-mediated down-regulation of downstream PEPCK and G-6-pase. In HepG2 cells, the quercetin (5 μM)-EGCG (5 μM) co-treatment exerted greater suppression on PA-induced changes in glucose and glycogen contents and hexokinase and G-6-pase activities than quercetin/EGCG alone (each 10 μM). The quercetin-EGCG co-treatment reduced glucose production through targeting FOXO1 and inhibiting the transcription of gluconeogenic enzymes. MiR-27a-3p and miR-96–5p regulated directly FOXO1 expression and function, and co-inhibition of miR-27a-3p and miR-96–5p weakened greatly the protective effect of quercetin-EGCG combination. This is the first report on the contributions of miR-27a-3p and miR-96–5p to the synergistic and protective effect of the quercetin-EGCG co-treatment against PA-induced insulin resistance through inhibiting FOXO1 expression.

槲皮素和 EGCG 表现出抗糖尿病和抗肥胖的活性，然而，它们在抗糖尿病/抗肥胖作用中的交互作用和潜在机制仍不清楚。本研究旨在填补这些知识空白。槲皮素、EGCG 或其组合在高脂高果糖饮食 (HFFD) 喂养的 C57BL/6 小鼠和棕榈酸 (PA) 处理的 HepG2 细胞中减弱胰岛素抵抗并减少肝糖异生。在小鼠中，补充槲皮素 (0.05%w/w)、EGCG (0.05%w/w) 及其组合 (槲皮素 0.05%+EGCG 0.05%w/w) 可减少体重增加和空腹血糖并改善血清生化参数。与单独使用槲皮素/EGCG 相比，槲皮素-EGCG 组合通过以下途径在更大程度上减少了糖异生。IRS-1/Akt/FOXO1 介导的下游 PEPCK 和 G-6-pase 下调。在 HepG2 细胞中，槲皮素 (5 μM)-EGCG (5 μM) 联合处理对 PA 诱导的葡萄糖和糖原含量变化以及己糖激酶和 G-6-pase 活性的抑制作用大于单独使用槲皮素/EGCG（各 10 μM） ）。槲皮素-EGCG 联合治疗通过靶向 FOXO1 和抑制糖异生酶的转录来减少葡萄糖的产生。MiR-27a-3p和miR-96-5p直接调节FOXO1的表达和功能，miR-27a-3p和miR-96-5p的共同抑制大大削弱了槲皮素-EGCG组合的保护作用。这是关于 miR-27a-3p 和 miR-96-5p 对槲皮素-EGCG 联合治疗通过抑制 FOXO1 表达对 PA 诱导的胰岛素抵抗的协同和保护作用的贡献的第一份报告。