Wnt Signaling Protects 3T3-L1 Preadipocytes from Apoptosis through Induction of Insulin-like Growth Factors

Abstract

Ectopic expression of Wnt-1 in 3T3-L1 preadipocytes stabilizes ␤-catenin, activates TCF-dependent gene transcription, and blocks adipogenesis. Here we report that upon serum withdrawal, Wnt-1 causes 3T3-L1 cells to resist apoptosis through a mechanism that is partially dependent on phosphatidylinositol 3-kinase. Although activation of Wnt signaling by inhibition of GSK-3 activity or ectopic expression of dominant stable ␤-catenin blocks apoptosis, inhibition of Wnt signaling through expression of dominant negative TCF-4 increases apoptosis. Wnt-1 stimulates 3T3-L1 preadipocytes to secrete factors that increase PKB/Akt phosphorylation at levels comparable with treatment with 10% serum. With DNA microarrays, we identified several secreted antiapoptotic genes that are induced by Wnt-1, notably insulinlike growth factor I (IGF-I) and IGF-II. Consistent with IGFs mediating the antiapoptotic effects of Wnt-1 in preadipocytes, conditioned medium from Wnt-1 expressing 3T3-L1 cells was unable to promote protein kinase B phosphorylation after the addition of recombinant IG-FBP-4. Thus, we demonstrated that Wnt-1 induces expression of antiapoptotic genes in 3T3-L1 preadipocytes such as IGF-I and IGF-II, which allows these cells to resist apoptosis in response to serum deprivation.

Cellular demise and inflammatory microglial activation during β-amyloid toxicity are governed by Wnt1 and canonical signaling pathways

“…Evidence for the dependence of Wnt1 on the Akt pathway can be drawn from a variety of cell populations. For example, PC12 cell differentiation that is dependent upon Wnt1 signaling and trophic factor induction is blocked during the repression of Akt activity [38], Wnt1 has been shown in preadipocytes to increase Akt phosphorylation [39], and the Wnt1-induced secreted protein in a fibroblast cell line uses Akt to block apoptotic death [40]. We show that Wnt1 overexpression independently increases the phosphorylation and the activation of Akt1 to a significantly greater degree than Aβ 1-42 alone, suggesting that Wnt1 uses Akt1 activation to promote neuronal protection.…”

The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/β-catenin pathway

“…Activation of selected target genes, such as Cyclin-D1 (Shtutman et al, 1999;Tetsu and McCormick, 1999), IGF2 (Longo et al, 2002) and TCF4 (Kolligs et al, 2002) was measured by real-time semi quantitative PCR ( Figure 2c). Significant increases of Cyclin-D1 (2.45 ± 0.32-and 1.86 ± 0.25-fold increase) and IGF2 expression (2.9 ± 0.07-and 1.38 ± 0.09-fold increase) were detected in LAN-1-R and IGRN-91-R, respectively.…”

Regulation of insulin secretion, glucokinase gene transcription and beta cell proliferation by adipocyte-derived Wnt signalling molecules

“…Adipocytes are hormonally active and adipocytokines are able to elicit a response from beta cells [5]. Studies have shown that adipocytes secrete Wnt signalling molecules to regulate adipocyte differentiation [9][10][11]. In a previous study we demonstrated that Wnt3a and Wnt10b are secreted by mature human adipocytes and regulate hormone secretion from adrenocortical cells in vitro [12].…”