Integration of Metabolomics and Transcriptomics Reveals the Mechanisms by Which Tetrandrine, Identified from Fangji Huangqi Decoction, Ameliorates Lipid Accumulation in Adipocytes

Abstract

Fangji Huangqi decoction (FHD) is a classic clinical formula used in traditional Chinese medicine to treat obesity. In this study, we aimed to screen active substances in FHD that are effective in treating obesity and to elucidate the mechanisms underlying FHD-mediated amelioration of lipid accumulation in adipocytes. Ultra-high-performance liquid chromatography-Quadrupole-orbitrap mass spectrometry was used to identify the principal components and metabolites of FHD in rat liver and adipose tissues following oral administration. Network pharmacology was employed to identify potential pharmacodynamically active substances for the treatment of obesity, and cell-based experiments were conducted to validate their effects on ameliorating lipid accumulation in adipocytes. Transcriptomics and non-targeted metabolomics were further employed to elucidate the potential mechanisms underlying the FHD component-mediated amelioration of lipid accumulation in adipocytes. In total, 68 substances were identified in FHD, 18 components and 14 metabolites of FHD were detected in the plasma and tissues. Tetrandrine was identified in plasma and multiple adipose tissues. Oil red O staining and triglyceride assay indicated that tetrandrine could ameliorate lipid accumulation of adipocytes. Metabolomics results indicated that tetrandrine can promote lipid metabolism in adipocytes. Transcriptomic analysis revealed that tetrandrine significantly upregulates the fibroblast growth factor 21 ( Fgf21 ) gene and downregulates the peroxisome proliferator-activated receptor gamma signaling pathway-related genes. Tetrandrine, identified from FHD, ameliorates lipid accumulation in adipocytes by promoting FGF21-mediated thermogenesis and energy expenditure, as well as by inhibiting preadipocyte differentiation.