The Novel Secreted Adipokine WNT1-inducible Signaling Pathway Protein 2 (WISP2) Is a Mesenchymal Cell Activator of Canonical WNT.
WNT1-inducible-signaling pathway protein 2 (WISP2) is primarily expressed in mesenchymal stem cells, fibroblasts, and adipogenic precursor cells. It is both a secreted and cytosolic protein, the latter regulating precursor cell adipogenic commitment and PPARγ induction by BMP4. To examine the effect of the secreted protein, we expressed a full-length and a truncated, non-secreted WISP2 in NIH3T3 fibroblasts. Secreted, but not truncated WISP2 activated the canonical WNT pathway with increased β-catenin levels, its nuclear targeting phosphorylation, and LRP5/6 phosphorylation. It also inhibited Pparg activation and the effect of secreted WISP2 was reversed by the WNT antagonist DICKKOPF-1. Differentiated 3T3-L1 adipose cells were also target cells where extracellular WISP2 activated the canonical WNT pathway, inhibited Pparg and associated adipose genes and, similar to WNT3a, promoted partial dedifferentiation of the cells and the induction of a myofibroblast phenotype with activation of markers of fibrosis. Thus, WISP2 exerts dual actions in mesenchymal precursor cells; secreted WISP2 activates canonical WNT and maintains the cells in an undifferentiated state, whereas cytosolic WISP2 regulates adipogenic commitment.
Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Center of Excellence for Cardiovascular and Metabolic Research, The Sahlgrenska Academy at the University of Gothenburg, SE-413 45 Gothenburg, Sweden.
John R
JR
Grünberg
Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Center of Excellence for Cardiovascular and Metabolic Research, The Sahlgrenska Academy at the University of Gothenburg, SE-413 45 Gothenburg, Sweden.
Ann
A
Hammarstedt
Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Center of Excellence for Cardiovascular and Metabolic Research, The Sahlgrenska Academy at the University of Gothenburg, SE-413 45 Gothenburg, Sweden.
Shahram
S
Hedjazifar
Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Center of Excellence for Cardiovascular and Metabolic Research, The Sahlgrenska Academy at the University of Gothenburg, SE-413 45 Gothenburg, Sweden. Electronic address: ulf.smith@medic.gu.se.
Ulf
U
Smith
D041721:3T3-L1 Cells; D050156:Adipogenesis; D054392:Adipokines / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D055511:CCN Intercellular Signaling Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D060508:Wnt3 Protein / Q000378:metabolism
D054392:Adipokines; D055511:CCN Intercellular Signaling Proteins; C413323:CCN5 protein, human; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D047495:PPAR gamma; D012097:Repressor Proteins; D060508:Wnt3 Protein
Adipose Tissue; Beta-catenin; Bone Morphogenetic Protein (BMP); Cell Biology; Obesity; Peroxisome Proliferator-activated receptor (PPAR); Wnt Pathway