Zanthoxylum schinifolium extracts enhance 3T3-L1 adipocyte differentiation via CHOP inhibition and PPARγ activation

Zanthoxylum schinifolium (ZS), which is widely used as a seasoning and traditional medicine in East Asia, has demonstrated pharmacological potential. This study investigated the effects of the leaf and twig extracts of ZS (LZSE and TZSE, respectively), which are native to the Honam region of Korea, on adipocyte differentiation and assessed the ligand-binding energy score of their components to bind peroxisome proliferator-activated receptor gamma (PPARγ), a critical regulator of adipogenesis and metabolic health. LZSE and TZSE were prepared using 70% ethanol, and their molecular effects on adipocyte differentiation were evaluated in 3T3-L1 preadipocytes. Single compounds from the extracts were identified using UPLC-ESI-Q-TOF-MS, and their ligand-binding energy scores were calculated via in silico molecular docking studies. PPARγ activity was further confirmed through reporter assays. LZSE and TZSE significantly promoted adipocyte differentiation, as demonstrated by morphological changes and the increased mRNA and protein levels of key adipogenic and lipogenic genes, such as PPARγ and CCAAT-enhancer-binding protein alpha (C/EBPα). LZSE specifically enhanced adipogenesis without inducing cytotoxicity, attributed to the inhibition of C/EBP homologous protein (CHOP) and stimulation of mitotic expansion. Additionally, UPLC-ESI-Q-TOF-MS identified several active compounds in LZSE and TZSE, and in silico docking revealed the high binding affinity of these compounds for the full-agonist ligand-binding domain of PPARγ. LZSE and TZSE could emerge as novel antidiabetic drug candidates based on their effects on adipocyte differentiation and PPARγ activation. Furthermore, the active compounds identified in these extracts hold promise as tentative PPARγ agonists, highlighting their therapeutic potential in the treatment of metabolic disorders.