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WISP1/CCN4 inhibits adipocyte differentiation through repression of PPARγ activity OPEN

Nathalie Ferrand 1 Véronique Béreziat 2 Marthe Moldes 2 Maurice Zaoui 1 Annette Larsen 1 Michèle Sabbah 1, *
* Corresponding author
1 Département Oncologie - Hématologie - Biologie et thérapeutiques du cancer [CRSA, Paris]
CR Saint-Antoine - Centre de Recherche Saint-Antoine, Sorbonne Universités, CHU Saint-Antoine [AP-HP]
2 Département Métabolisme - Inflammation - Equipe Lipodystrophies génétiques et acquises [CRSA, Paris]
CR Saint-Antoine - Centre de Recherche Saint-Antoine, Sorbonne Universités, CHU Saint-Antoine [AP-HP]
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. WISP1 (Wnt1-inducible signaling pathway protein-1, also 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. WISP1/CCN4 (hereafter referred to as WISP1) is both an intracellular and a secreted protein found in the extracellular matrix (ECM) and, like many other matricellular proteins able to modulate cellular responses such as cell growth, differentiation and survival 4. WISP1 is expressed in various normal tissues including heart, kidney, lung, pancreas, placenta, ovary, small intestine and spleen. Interestingly, elevated WISP1 expression has also been observed in a variety of cancers including hepatocellular carcinoma 5 , colon adenocarci-noma 3 , lung carcinoma 6 , breast cancer 7 and cholangiocarcinoma 8. Wnt signaling pathway plays a key role for maintaining the cells in an undifferentiated state 9. The Wnt proteins are secreted signaling factors that affect cell fate and differentiation, including adipogenesis, myogenesis and mammary development. When Wnt signaling is active, GSK-3β is inhibited, allowing β-catenin to accumulate in the nucleus where it binds to TCF-LEF transcription factors and activates Wnt-target genes. The Wnt-1 protein has been described as an inhibitor of adipocyte differentiation 9. Interestingly, ectopic expression of Wnt-1 in 3T3-L1 murine preadipocytes induced the expression of several downstream genes including WISP1 10 , thereby suggesting a potential role for WISP1 in adipocyte differentiation. Adipogenesis is characterized by dynamic changes in gene expression 11–13. It is well accepted that both peroxi-some proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein (C/EBPs) function as critical regulators of adipogenesis 14, 15. PPARs are members of the Nuclear Receptor family, comprising a subgroup of three homologous genes. Among them, PPARγ acts primarily as a master regulator of adipocyte differentiation and metabolism 15, 16. In particular, PPARγ is sufficient and necessary for fat cell differentiation. Following
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Nathalie Ferrand, Véronique Béreziat, Marthe Moldes, Maurice Zaoui, Annette Larsen, et al.. WISP1/CCN4 inhibits adipocyte differentiation through repression of PPARγ activity OPEN. Scientific Reports, Nature Publishing Group, 2017, 7 (1), pp.1749 - 1749. ⟨10.1038/s41598-017-01866-2⟩. ⟨inserm-01522805⟩

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