Polyphenol-Rich Extract of Fermented Chili Pepper Alleviates Insulin Resistance in HepG2 Cells via Regulating INSR, PTP1B, PPAR-gamma, and AMPK Pathways

Fermented Capsicum frutescens L. is a well-known traditional food ingredient in China with a variety of potential nutritional functions due to the increased content of polyphenolic compounds during the fermentation process. This study aimed to investigate the ameliorative effect of fermented chili peppers (FCP) on insulin resistance and the potential mechanism of action. HepG2 cells were treated with 5 x 10(-6) mol/L insulin for 12 h to establish the insulin resistance model. The results showed that the ethanol extract of FCP (1 mg/mL), rather than non-FCP extract, significantly increased glucose consumption in insulin-resistant HepG2 cells, which was at least partly attributed to an increase in polyphenolic compounds after fermentation, including kaempferol-3-O-rutinoside, caffeic acid, kaempferol-3-O-glucoside, luteolin, and apigenin. Molecular docking analysis suggested that these five significantly increased polyphenolic compounds in FCP could partially and effectively interact with the key amino acid residues of four key insulin resistance-related receptors (INSR, PTP1B, PPAR-gamma, and AMPK). In conclusion, the fermentation process enhanced or even conferred a pronounced anti-insulin resistance effect on chili peppers, and the increased polyphenolic compounds in chili pepper had synergistic effects in modulating the INSR, PTP1B, PPAR-gamma, and AMPK pathways to regulate the destruction of glucose consumption.