The Novel Secreted Adipokine WNT1-Inducible-Signaling Pathway Protein2/WISP2 is a Mesenchymal Cell Activator of Canonical WNT [Metabolism]

January 22nd, 2014 by Grunberg, J. R., Hammarstedt, A., Hed&jnodot;azifar, S., Smith, U.

WNT1-inducible-signaling pathway protein2/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, like WNT3a, promoted partial de-differentiation 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 while cytosolic WISP2 regulates adipogenic commitment.