Signaling by Wnt glycoproteins, which are important in development, is mediated by Frizzled receptors and the co-receptors low-density lipoprotein receptor–related protein 5 (LRP5) and LRP6. Canonical Wnt signaling depends on the inhibition of glycogen synthase kinase 3β (GSK-3β) and the subsequent stabilization of the transcriptional cofactor β-catenin. Wnt signaling blocks the differentiation of preadipocytes, and dysregulated Wnt signaling is associated with diabetes. Noting that the Wnt signaling pathway interacts with and regulates the insulin signaling pathway, Palsgaard et al. investigated crosstalk between both pathways in a mouse preadipocyte cell line. Western blotting analysis showed that Wnt3a and insulin individually stimulated the phosphorylation of similar molecules, including GSK-3β, Akt, and extracellular signal–regulated kinases 1 and 2 (ERK1/2); however, the kinetics of phosphorylation in response to Wnt3a were slower than those of insulin, and the extent of phosphorylation was less. Wnt3a-dependent phosphorylation of Akt was blocked in cells deficient in both the insulin receptor (IR) and the insulin-like growth factor 1 (IGF-1) receptor (IGF1R). In preadipocytes deficient in LRP5, insulin-dependent phosphorylation of GSK-3β, Akt, and ERK1/2 was reduced in extent compared with that in wild-type cells; however, loss of LRP5 had no effect on IGF-1–dependent phosphorylation of these targets. Coimmunoprecipitation studies showed that LRP5 physically interacted with either IR or IGF1R in preadipocytes under basal conditions. Treatment of preadipocytes with either Wnt3a or insulin increased the extent of the association between LRP5 and IR, but not between LRP5 and IGF1R. LRP5 and IR were also physically associated with each other in white fat tissue from mice. Together, these data suggest that the Wnt and insulin signaling pathways exhibit crosstalk in preadipocytes at the level of the Wnt co-receptor LRP5, which the authors suggest may act as a co-receptor for IR signaling.
J. Palsgaard, B. Emanuelli, J. N. Winnay, G. Sumara, G. Karsenty, C. R. Kahn, Cross-talk between insulin and Wnt signaling in preadipocytes. J. Biol. Chem. 287, 12016–12026 (2012). [Abstract] [Full Text]