WISP1/CCN4 inhibits adipocyte differentiation through repression of PPARγ activity

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.

The novel adipokine WISP1 associates with insulin resistance and impairs insulin action in human myotubes and mouse hepatocytes

“…The increased WISP1 expression in VAT of obese men is in line with previous reports from our group and others [13][14][15]26] suggesting that WISP1 expression is regulated by body weight. High-fat feeding in mice increased the expression of WISP1 in adipose tissue [13,27] while diet-induced weight loss in humans lowered WISP1 expression in adipose tissue [13]. The present study also detailed the relationship between WISP1 and insulin sensitivity.…”

“…Here, we used WISP1 concentrations representative of the levels found in the circulation whereas the 3T3-L1 adipocytes were exposed to supraphysiological concentrations of WISP1. Moreover, different signalling pathways might be involved in the actions of WISP1 in various cell types [27]. Importantly, the impaired insulin-mediated Akt phosphorylation in primary hSkMCs and AML12 hepatocytes was accompanied by inhibition of the phosphorylation of several of its well-characterised substrates.…”

Breast-Associated Adipocytes Secretome Induce Fatty Acid Uptake and Invasiveness in Breast Cancer Cells via CD36 Independently of Body Mass Index, Menopausal Status and Mammary Density

“…Cells were differentiated into adipocytes by culturing them in adipogenic induction medium for four days in DMEM high glucose supplemented with 10% Fetal Bovine Serum (FBS) 2 mmol/L glutamine, penicillin/streptomycin (All from Gibco, Invitrogen Corporation, San Diego, CA, USA), 1 µM dexamethasone, 250 µM isobutylmethylxanthine (IBMX), 1 µM insulin and 1 µM rosiglitazone (all from Sigma-Aldrich, Saint-Louis, MO, USA), followed by an adipogenic maintenance medium (1 µM insulin and 1 µM rosiglitazone in DMEM high glucose and 10% FBS). After 14 days, adipogenic differentiation was evaluated by measuring the lipid accumulation using Oil-red-O (Sigma-Aldrich) as described previously [57,58]. Lipid droplet analysis was performed on fixed, Oil Red O-and DAPI-stained cells with cellSens Dimension v1.16 (Shinjuku, Tokyo, Japan).…”

“…After transfer onto nitrocellulose membrane, blots were incubated overnight at 4 • C with the appropriate antibody, followed by incubation with a horseradish peroxidase-conjugated secondary antibody (1/2000, Cell Signaling, Danvers, MA, USA). Bands were visualized using the Clarity™ Western ECL substrate (BIO-RAD, Hercules, CA, USA) on Chemidoc systems [58]. Protein expression was quantified by densitometric analysis of the immunoblots using Image Lab software developed by Bio-Rad.…”

Remodeling adipose tissue inflammasome for type 2 diabetes mellitus treatment: Current perspective and translational strategies

“…Another novel adipokine, wingless‐related integration site‐1 (WNT‐1)‐inducible signaling pathway protein‐1 (WISP1), also known as CCN4, was shown to inhibit adipogenesis by preventing adipocyte differentiation and block PPAR‐γ transcriptional activity, thus believed to contribute toward the development of obesity . The proinflammatory potential of the adipokine was exhibited in vitro, when macrophages treated with WISP1 caused increased secretion of proinflammatory cytokines in a dose‐dependent fashion and polarized them to M1 phenotype .…”