Abstract
Wnt signaling has been reported to block apoptosis and regulate differentiation of mesenchymal progenitors through inhibition of glycogen synthase kinase 3 and stabilization of beta-catenin. The effects of Wnt in preadipocytes may be mediated through Frizzled (Fz) 1 and/or Fz2 as these Wnt receptors are expressed in preadipocytes and their expression declines upon induction of differentiation. We ectopically expressed constitutively active chimeras between Wnt8 and Fz1 or Fz2 in preadipocytes and mesenchymal precursor cells. Our results indicated that activated Fz1 increases stability of beta-catenin, inhibits apoptosis, induces osteoblastogenesis, and inhibits adipogenesis. Although activated Fz2 does not influence apoptosis or osteoblastogenesis, it inhibits adipogenesis through a mechanism independent of beta-catenin. An important mediator of the beta-catenin-independent pathway appears to be calcineurin because inhibitors of this serine/threonine phosphatase partially rescue the block to adipogenesis caused by Wnt3a or activated Fz2. These data supported a model in which Wnt signaling inhibits adipogenesis through both beta-catenin-dependent and beta-catenin-independent mechanisms.
Highlights
Wnts are a family of secreted proteins that act through paracrine and autocrine mechanisms to regulate many aspects of cell fate and development [1]
Our results indicated that activated Fz1 increases stability of -catenin, inhibits apoptosis, induces osteoblastogenesis, and inhibits adipogenesis
Inhibition of -catenin signaling with a dominant negative TCF causes spontaneous adipogenesis [6], suggesting that endogenous Wnts act to repress preadipocyte differentiation
Summary
Fz, Frizzled; LRP, lipoprotein receptorrelated protein; TCF, T-cell factor; LEF, lymphoid-enhancing factor; C/EBP, CCAAT/enhancer-binding protein; PPAR, peroxisome proliferator-activated receptor; NFAT, nuclear factor of activated T; TUNEL, terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling associated with Wnt family members such as Wnt, Wnt3a, and Wnt10b and frizzled receptors such as Fz1 and Fz5 [1]. In response to inducers of adipogenesis, there is a transient induction of CCAAT/enhancer-binding protein  (C/EBP) and C/EBP␦, which independently activate expression of C/EBP␣ and peroxisome proliferator-activated receptor ␥ (PPAR␥). These master adipogenic transcription factors regulate each other’s expression through a positive feedback loop. Quired to mimic the complete block to adipogenesis observed with Wnt10b These data suggested that Wnts inhibit adipocyte conversion through -catenin-dependent and -independent mechanisms. This study suggested that some effects of Wnt on mesenchymal cell fate can be attributed to -catenin-dependent signaling by Fz1, whereas other effects, such as inhibition of adipogenesis, involve activation of more than one Fz and signaling pathway
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