Zhaqu compound improves glucose and lipid metabolism in T2DM with MASLD by modulating gut microbiota and PPARγ

Introduction Zhaqu Compound (ZQC), a traditional Chinese herbal formula, has shown promise in improving glucose and lipid metabolism, but its mechanisms in T2DM-MASLD remain unclear. Methods In this study, db/db mice with T2DM-MASLD were treated for 12 weeks with ZQC, metformin, or saline. Metabolic outcomes included blood glucose, insulin resistance indices, lipid profiles, hepatic steatosis, hepatocyte ultrastructure, gut microbiota (16S rRNA), fecal metabolomics, and liver transcriptomics. In high-glucose + palmitate–induced HepG2 cells, ZQC-containing serum and the PPARγ agonist GW1929 were applied to assess gluconeogenic and lipogenic proteins. Results ZQC improved glycemia, insulin resistance, lipid profiles, and hepatic steatosis. Gut microbiota analysis showed modulation of key metabolic genera, including Bacteroides, Mucispirillum, Lactobacillus, Lachnospiraceae , and Muribaculaceae , with correlations to glucose, lipid, and hepatic biochemical indices. Metabolomics and transcriptomics revealed regulation of amino acid metabolism, AGE-RAGE/mTOR pathways, and enrichment of hepatic PPARγ–related pathways, alongside modulation of fatty acid and arachidonic acid metabolism. In HepG2 cells, ZQC reduced lipid accumulation, decreased triglycerides and cholesterol, enhanced glucose uptake, and restrained PPARγ and its downstream transporters CD36 and FABP4. N-phenethylhexadecanamide, palmitic acid, and isoxanthohumol likely mediate these effects. Discussion Overall, ZQC improves glucose and lipid metabolism in T2DM with MASLD by modulating gut microbiota, influencing hepatic PPARγ–related pathways, and enhancing hepatocyte metabolic function.