WISP2 regulates preadipocyte commitment and PPARγ activation by BMP4

Abstract

Inability to recruit new adipose cells following weight gain leads to inappropriate enlargement of existing cells (hypertrophic obesity) associated with inflammation and a dysfunctional adipose tissue. We found increased expression of WNT1 inducible signaling pathway protein 2 (WISP2) and other markers of WNT activation in human abdominal s.c. adipose tissue characterized by hypertrophic obesity combined with increased visceral fat accumulation and insulin resistance. WISP2 activation in the s.c. adipose tissue, but not in visceral fat, identified the metabolic syndrome in equally obese individuals. WISP2 is a novel adipokine, highly expressed and secreted by adipose precursor cells. Knocking down WISP2 induced spontaneous differentiation of 3T3-L1 and human preadipocytes and allowed NIH 3T3 fibroblasts to become committed to the adipose lineage by bone morphogenetic protein 4 (BMP4). WISP2 forms a cytosolic complex with the peroxisome proliferator-activated receptor γ (PPARγ) transcriptional activator zinc finger protein 423 (Zfp423), and this complex is dissociated by BMP4 in a SMAD-dependent manner, thereby allowing Zfp423 to enter the nucleus, activate PPARγ, and commit the cells to the adipose lineage. The importance of intracellular Wisp2 protein for BMP4-induced adipogenic commitment and PPARγ activation was verified by expressing a mutant Wisp2 protein lacking the endoplasmic reticulum signal and secretion sequence. Secreted Wnt/Wisp2 also inhibits differentiation and PPARγ activation, albeit not through Zfp423 nuclear translocation. Thus adipogenic commitment and differentiation is regulated by the cross-talk between BMP4 and canonical WNT signaling and where WISP2 plays a key role. Furthermore, they link WISP2 with hypertrophic obesity and the metabolic syndrome. mesenchymal stem cells | adipogenesis

Increased fat cell size: a major phenotype of subcutaneous white adipose tissue in non-obese individuals with type 2 diabetes

“…In line with this, previous studies suggest that impaired adipogenesis linked to WNT-signalling and peroxisome proliferatoractivated receptor γ (PPARγ) activation may play a role [40,41]. Bone morphogenetic protein 4 plays a critical part in early adipogenesis by dissociating WNT1-inducible signalling pathway protein 2 (a negative regulator of adipogenesis) and zinc finger protein 423 (ZNF423), thus allowing ZNF423 to relocate to the nucleus and start the adipogenesis programme [16,40,41]. In addition, early B cell factor 1 (EBF1) is a well-described regulator of adipogenesis [42], and we recently observed that reduced EBF1 levels and activity promote scWAT hypertrophy in part via interactions involving PPARγ [43].…”

“…Defective subcutaneous fat mass expandability has been proposed as a mechanism explaining ectopic fat accumulation and development of type 2 diabetes. In line with this, previous studies suggest that impaired adipogenesis linked to WNT-signalling and peroxisome proliferatoractivated receptor γ (PPARγ) activation may play a role [40,41]. Bone morphogenetic protein 4 plays a critical part in early adipogenesis by dissociating WNT1-inducible signalling pathway protein 2 (a negative regulator of adipogenesis) and zinc finger protein 423 (ZNF423), thus allowing ZNF423 to relocate to the nucleus and start the adipogenesis programme [16,40,41].…”

The Novel Secreted Adipokine WNT1-inducible Signaling Pathway Protein 2 (WISP2) Is a Mesenchymal Cell Activator of Canonical WNT

“…Importantly, this was not due to lack of adipogenic precursor cells but to an inability to inhibit canonical WNT activation in these cells and to activate the expression of important secreted WNT antagonists, in particular, DICKKOPF-1. In further support of this concept, we found WNT1-inducible-signaling pathway protein 2 (WISP2), frequently used as a marker of canonical WNT activation (12), to be increased in the subcutaneous adipose tissue precursor cells and positively associated with insulin resistance and amount of ectopic fat accumulation (13). We also found WISP2 to be a secreted protein, highly expressed in mesenchymal stem cells, fibroblasts, and preadipocytes and adipogenic differentiation was associated with a marked reduction in Wisp2 expression, whereas differentiation was inhibited by extracellular WISP2.…”

“…WISP2 was also recently identified in a proteomics analysis of the secretome of human adipose tissue (14) and can thus be considered a novel secreted adipokine. However, the overall regulation of Wisp2 expression is unclear although canonical WNT ligands can increase it (12,13).…”

Longitudinal muscle gene expression patterns associated with differential intramuscular fat in cattle

“…WISP2 is known to be highly expressed in human preadipocytes. It has recently been discovered to encode a novel secreted adipokine protein that is a negative regulator of preadipocyte commitment (Hammarstedt et al, 2013). It has also been shown to inhibit the pro-fibrotic connective tissue growth factor (Sabbah et al, 2011).…”