WISP1/CCN4 inhibits adipocyte differentiation through repression of PPARγ activity

WISP1 (Wnt1-inducible signaling pathway protein-1, also known as CCN4) is a member of the CCN family able to mediate cell growth, transformation and survival in a tissue-specific manner. Here, we report that WISP1 expression was highly increased in preadipocytes and decreased during adipocyte differentiation. Moreover, we observed an increase in WISP1 gene expression in adipose tissue from both diet-induced and leptin-deficient ob/ob obese mice, suggesting that WISP1 could be involved in the pathophysiological onset of obesity. Interestingly, overexpression of WISP1 in 3T3-F442A cells prevented adipocyte differentiation via downregulation of peroxisome proliferator-activated receptor (PPAR gamma) transcriptional activity thereby attenuating the expression of adipogenic markers. Conversely, silencing of WISP1 enhanced adipocyte differentiation. We further show that the inactivation of PPAR gamma transcriptional activity was mediated, at least in part, by a direct physical association between WISP1 and PPAR gamma, followed by proteasome-dependent degradation of PPAR gamma. These results suggest for the first time that WISP1 interacts with PPAR gamma and that this interaction results in the inhibition of PPAR gamma activity. Taken together our results suggest that WISP1 functions as a negative regulator of adipogenesis.