Pygo2 Regulates Adipogenesis Via β-Catenin-Axin2-GSK3β Signaling Pathway

Wnt/β-Catenin signaling plays a key role in regulating adipocyte differentiation through indirectly inhibiting the expression of CCAAT/enhancer-binding protein α(C/EBPα)and peroxisome proliferator-activated receptor γ(PPARγ).However,the mechanism by which Wnt/β-Catenin signaling inhibits the expression of C/EBPα and PPARγ remains poorly understood.Moreover,the factor(s)that determines the Wnt/β-Catenin output level during adipogenesis is also not completely defined.In the present study,we showed that Pygopus2(Pygo2),the newly identified Wnt/β-Catenin component,exhibited a declined expression pattern during adipocyte differentiation,resulting in an attenuated Wnt/β-Catenin output level.Our study also showed that ectopic expression of Pygo2 attenuated adipocyte differentiation,whereas knockdown of Pygo2 enhanced the differentiation process and induced spontaneous differentiation.Mechanism study indicated that Pygo2 inhibition led to the downregulation of Axin2,a constitutive Wnt target,in the cytoplasm.Consequently,Axin2-bound glycogen synthase kinase-3β(GSK3β)was released and translocated into the nucleus to phosphorylate C/EBPβ and Snail,resulting in an increase in the DNA binding activity of C/EBPβ and decreased protein stability of Snail.Thus,Pygo2 inhibition resulted in adipocyte differentiation because C/EBPβ could directly activate the expression of C/EBPα and PPARγ,whereas Snail could directly suppress the expression of PPARγ.Consistent with this,embryonic fibroblasts from Pygo2-/-mice exhibited spontaneous adipocyte differentiation,and adipocyte precursor-specific Pygo2 deficient mice exhibited increased adiposity with augmented expression of C/EBPα and PPARγ as well as their down-stream target genes.We further showed impaired glucose tolerance and decreased systemic insulin sensitivity in Pygo2 deficient mice.Our study revealed an association between C/EBPα/PPARγ expression and Wnt/β-Catenin activation,which highlights the role of Wnt/β-Catenin in the regulation of adipocyte differentiation.Our study also provided a possibility that Pygo2 may act as a novel target for the treatment of obesity and diabetes.