Wnt/β-catenin signaling plays a distinct role in methyl gallate-mediated inhibition of adipogenesis.
The canonical Wnt/β-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 β-catenin signaling plays a distinct role in methyl gallate (MG)-mediated inhibition of 3T3-L1 adipocytes differentiation. We found that the expression of β-catenin decreased after adipogenic hormonal induction, whereas incubation of the differentiating cells with a physiological concentration of MG during adipogenic hormonal induction significantly prevented β-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 β-catenin caused by phosphorylation at serine-33. In addition, MG treatment led to phosphorylation of GSK3β, which is one of β-catenin-degrading enzymes. Consequently, MG treatment facilitated translocation of the stabilized β-catenin from the cytoplasm to nucleus, and activates its target genes cyclin D1 and c-Myc. Furthermore, MG-induced stabilization of β-catenin suppresses PPARγ expression. Moreover, pharmacological activation or inhibition of β-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/β-catenin signaling, and therefore represents a promising therapeutic agent in obesity.
Department of Microbiology, College of Medicine, Soonchunhyang University, South Korea; Institute of Tissue Regeneration, College of Medicine, Soonchunhyang University, South Korea.
Miso
M
Jeon
Department of Microbiology, College of Medicine, Soonchunhyang University, South Korea; Institute of Tissue Regeneration, College of Medicine, Soonchunhyang University, South Korea.
Naimur
N
Rahman
Department of Microbiology, College of Medicine, Soonchunhyang University, South Korea; Institute of Tissue Regeneration, College of Medicine, Soonchunhyang University, South Korea. Electronic address: yongsikkim@sch.ac.kr.
Yong-Sik
YS
Kim
D041721:3T3-L1 Cells; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects* / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D000072261:Dishevelled Proteins / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D051157:Frizzled Receptors / Q000235:genetics; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics; D051379:Mice; D018613:Microscopy, Confocal; D047495:PPAR gamma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000235:genetics; D051155:Wnt1 Protein / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D000072261:Dishevelled Proteins; C000606579:Dvl1 protein, mouse; D051157:Frizzled Receptors; C489739:Fzd1 protein, mouse; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; D047495:PPAR gamma; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D051176:beta Catenin; D012694:Serine; C052082:methyl gallate; D005707:Gallic Acid; D000071679:Glycogen Synthase Kinase 3 beta
Adipogenesis; Methyl gallate; PPARγ; Wnt/β-catenin