Total Saponins from Panax Japonicus Regulate β-Oxidation in Adipocytes through the miR192-3p/GSK3β Pathway

Hyperlipidemia, a major component of metabolic syndrome, poses a substantial global public health challenge. Total saponins from Panax japonicus C.A. Mey. (TSPJ) have been reported to improve lipid metabolism, but the underlying mechanisms are not fully understood. This study investigated whether TSPJ promote fatty acid β-oxidation in mouse and adipocyte models and explored the involvement of the microRNA-192-3p (miR-192-3p) / glycogen synthase kinase-3 beta (GSK3β) pathway. Hyperlipidemia was induced in mice using high-fat-diet (HFD), and in those mice, TSPJ reduced body weight, epididymal fat index, and serum triglyceride (TG), total cholesterol (CHO) and low-density lipoprotein cholesterol (LDL-C) levels, while increasing high-density lipoprotein cholesterol (HDL-C) and β-hydroxybutyrate (β-HB) concentrations and upregulating key β-oxidation enzymes in epididymal white adipose tissue. Cell models were created by inducing 3T3-L1 adipocytes with palmitic acid (PA), and in those cells, TSPJ decreased lipid droplet accumulation and similarly enhanced the expression of β-oxidation-related enzymes. Mechanistically, TSPJ upregulated miR-192, suppressed GSK3β expression, increased GSK3β phosphorylation at Ser9, and thereby promoted the expression of β-oxidation enzymes. Knockdown of miR-192 abrogated the effects of TSPJ on GSK3β signaling, β-oxidation, and lipid accumulation, but additional knockdown of GSK3β restored β-oxidation and attenuated lipid deposition. These findings demonstrate that TSPJ enhances mitochondrial fatty acid β-oxidation via the miR-192-3p/GSK3β pathway, supporting its potential as a therapeutic candidate for hyperlipidemia.