Pygo2 Regulates Adiposity and Glucose Homeostasis via -Catenin-Axin2-GSK3 Signaling Pathway

Wnt/-catenin signaling plays a key role in regulating adipogenesis through indirectly inhibiting the expression of C/EBP and peroxisome proliferator-activated receptor (PPAR); however, the detailed molecular mechanism remains poorly understood. Moreover, the factor(s) that determines the Wnt/-catenin output level during adipogenesis is also not completely defined. In this study, we showed that Pygo2 exhibited a declined expression pattern during adipocyte differentiation, resulting in an attenuated Wnt/-catenin output level. The mechanism study indicated that Pygo2 inhibition led to the downregulation of Axin2, a constitutive Wnt target, in the cytoplasm. Consequently, Axin2-bound GSK3 was released and translocated into the nucleus to phosphorylate C/EBP and Snail, resulting in an increase in the DNA binding activity of C/EBP and decreased protein stability of Snail, which subsequently activated the expression of C/EBP and PPAR. Consistent with this, embryonic fibroblasts from Pygo2(-/-) mice exhibited spontaneous adipocyte differentiation, and adipocyte precursor-specific Pygo2-deficient mice exhibited increased adiposity with decreased energy expenditure. We further showed impaired glucose tolerance and decreased systemic insulin sensitivity in Pygo2-deficient mice. Our study revealed an association between Pygo2 function and obesity or diabetes.