Toosendanin inhibits adipogenesis by activating Wnt/β-catenin signaling

Toosendanin (TSN), a triterpenoid extracted from Melia toosendan, has been reported to possess antioxidant, anti-inflammatory, anti-allergic, and anti-arthritic activities. However, its anti-adipogenic effect remains unknown. Here, we found that TSN dose-dependently attenuated lipid accumulation in preadipocytes 3T3-L1 as evidenced by Oil Red O staining. TSN also significantly downregulated mRNA and protein levels of adipocytokines (adiponectin and leptin), CCAAT/enhancer binding proteins a (C/EBP-alpha), peroxisome proliferator-activated receptor. (PPAR-gamma), fatty acid synthase, and acetyl-CoA carboxylase in adipocytes. To understand the mechanism, we observed that TSN effectively activated Wnt/beta-catenin pathway, in which TSN increased low density lipoprotein receptor related protein 6, disheveled 2, beta-catenin, and cyclin D1 expression levels, while it inactivated glycogen synthase kinase 3 beta by enhancing its phosphorylation. Moreover, TSN reduced weight of gonadal white fat and serum triacylglycerol (TAG) content in high-fat diet (HFD)-fed mice. Interestingly, the in vivo studies also demonstrated that TSN promoted the expression of beta-catenin, but accordingly repressed C/EBP-alpha and PPAR-gamma expression in HFD-induced mice. Overall, TSN is capable of inhibiting the lipogenesis of adipocytes by activating the Wnt/beta-catenin pathway, suggesting potential application of TSN as a natural anti-obesity agent.