Wnt/ß-catenin signaling plays a distinct role in methyl gallate-mediated inhibition of adipogenesis.

ABSTRACT

The canonical Wnt/ß-catenin signaling not only features in many developmental processes but also recently emerged as an attractive negative regulator of differentiation of preadipocytes into adipocytes. Here, we show that ß-catenin signaling plays a distinct role in methyl gallate (MG)-mediated inhibition of 3T3-L1 adipocytes differentiation. We found that the expression of ß-catenin decreased after adipogenic hormonal induction, whereas incubation of the differentiating cells with a physiological concentration of MG during adipogenic hormonal induction significantly prevented ß-catenin degradation by activating Wnt signaling components such as Wnt1, Wnt10b, Fzd1, Fzd2, Lrp5, Lrp6, Dvl1, and Dvl2. Mechanistic experiments revealed that MG treatment during early adipocytic differentiation specifically inhibited degradation of ß-catenin caused by phosphorylation at serine-33. In addition, MG treatment led to phosphorylation of GSK3ß, which is one of ß-catenin-degrading enzymes. Consequently, MG treatment facilitated translocation of the stabilized ß-catenin from the cytoplasm to nucleus, and activates its target genes cyclin D1 and c-Myc. Furthermore, MG-induced stabilization of ß-catenin suppresses PPARγ expression. Moreover, pharmacological activation or inhibition of ß-catenin signaling during adipocytes differentiation decreased and increased, respectively, the level of the key adipogenic marker, PPARγ, and of its downstream targets, aP2 and adiponectin while MG treatment effectively reversed their expression level. Collectively, our data suggest that MG is a novel pharmacological stimulator of canonical Wnt/ß-catenin signaling, and therefore represents a promising therapeutic agent in obesity.