WISP1/CCN4 inhibits adipocyte differentiation through repression of PPAR\u03b3 activity

Nathalie Ferrand,Véronique Béreziat,Maurice Zaoui,Michèle Sabbah,Annette K Larsen,Marthe Moldes

doi:10.1038/s41598-017-01866-2

Abstract

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 (PPARγ) transcriptional activity thereby attenuating the expression of adipogenic markers. Conversely, silencing of WISP1 enhanced adipocyte differentiation. We further show that the inactivation of PPARγ transcriptional activity was mediated, at least in part, by a direct physical association between WISP1 and PPARγ, followed by proteasome-dependent degradation of PPARγ. These results suggest for the first time that WISP1 interacts with PPARγ and that this interaction results in the inhibition of PPARγ activity. Taken together our results suggest that WISP1 functions as a negative regulator of adipogenesis.

Highlights

WISP1 (Wnt1-inducible signaling pathway protein-1, known as CCN4) is a member of the connective tissue growth factor/cystein-rich 61/nephroblastoma overexpressed (CCN) family[1]
We first determined whether WISP1 was expressed in both visceral (VAT) and subcutaneous adipose tissues (SAT) in mice
The levels of WISP1 mRNA decreased during adipocyte differentiation, in contrast to the expression of the ADIPOQ gene that increased during the same period (Fig. 1b)

Summary

Introduction

WISP1 (Wnt1-inducible signaling pathway protein-1, known as CCN4) is a member of the connective tissue growth factor/cystein-rich 61/nephroblastoma overexpressed (CCN) family[1]. The CCN family is composed of six members, Cyr61/CCN1, CTGF/CCN2, NOV/CCN3, WISP1/CCN4, WISP2/CCN5 and WISP3/CCN6, referred to as CCN1-6, based on the unified nomenclature[2] Three of these proteins, WISP1-3, were initially identified in C57MG cells, a mouse mammary epithelial cell line with Wnt-1 expression, and subsequently shown to be Wnt-1-induced genes[3]. The Wnt proteins are secreted signaling factors that affect cell fate and differentiation, including adipogenesis, myogenesis and mammary development. Our results indicate that WISP1 interacts with PPARγ, mediates proteasome-dependent degradation of PPARγ, thereby reducing PPARγ protein level and activity Using both genetic and diet-related mouse models of obesity we found that WISP1 expression increases with obesity and may contribute to the dysregulation of adipocyte function

Methods

Results

Conclusion