Miao Sour Soup Modulates Hepatic Gluconeogenesis Through PI3K/Akt/Foxo1 Signaling in High-Fat Diet-Induced Rats

Miao Sour Soup (MSS) is a traditional fermented dish containing bioactive constituents such as lycopene, capsaicin, and short-chain fatty acids, which have been associated with anti-obesity, anti-inflammatory, and antioxidant effects. Excessively elevated hepatic gluconeogenesis is a critical element instigating energy metabolism dysregulation in the body. This research examined the extent to which MSS enhances energy metabolism abnormalities caused by a high-fat diet via hepatic gluconeogenesis and confirmed this route. The findings indicated that MSS intervention markedly decreased hepatic lipid accumulation, pro-inflammatory cytokine secretion, and blood lipid and glucose levels in rats subjected to a high-fat diet. Non-targeted metabolomics study revealed that MSS influences energy metabolism pathways, including glycolysis and gluconeogenesis. Subsequently, Western blot analysis was conducted to assess protein expression in the NF-κB inflammatory pathway and the PI3K/Akt/Foxo1 signaling pathway. The findings indicated that MSS decreased NF-κB expression in the livers of rats subjected to a high-fat diet, thereby activating the PI3K/Akt/Foxo1 signaling pathway and decreasing the expression of PEPCK and G6PC, essential proteins in gluconeogenesis. This study's results demonstrate that Foxo1 is a crucial protein in the dysregulation of glucose metabolism caused by lipid metabolism diseases. MSS may stimulate the PI3K/Akt/Foxo1 signaling pathway by mitigating chronic inflammation caused by a high-fat diet, therefore inhibiting excessive hepatic gluconeogenesis and ultimately improving insulin resistance.