Geniposidic Acid Reduces Lipid Accumulation and Is Associated with Altered AMPK Phosphorylation in 3T3-L1 Adipocytes

Obesity is a chronic metabolic disorder characterized by excessive adipose tissue accumulation and dysregulated lipid metabolism. This study investigated the effects of geniposidic acid (GA) on intracellular lipid accumulation and associated molecular responses during 3T3-L1 adipocyte differentiation. MDI-induced cells were treated with GA (2.5–10 μg/mL) and evaluated using lipid staining, RT-qPCR, Western blot, and JC-1 assays, alongside network pharmacology and computational analyses. Network analysis identified 57 overlapping GA-associated and obesity-related candidate targets, including associations with PPAR signaling. GA reduced intracellular lipid accumulation, with significant reductions at 5 and 10 μg/mL. Gene and protein expression analyses revealed decreases in adipogenic and lipogenic markers and increases in selected fatty acid metabolism-related markers. GA also attenuated the loss of mitochondrial membrane potential at 10 μg/mL. The p-AMPKα/AMPKα ratio was 1.28-fold that of the MDI-treated group at 10 μg/mL, whereas lower concentrations did not show a consistent increase. Docking scores for PPARα and PPARγ were −7.634 and −6.735 kcal/mol, respectively, and the modeled complexes were evaluated over 200 ns. These findings suggest that GA may reduce lipid accumulation and alter metabolic markers, supporting its potential as a natural bioactive compound for further investigation in obesity-related metabolic dysfunction.