Cross-talk between insulin and Wnt signaling in preadipocytes: role of Wnt co-receptor low density lipoprotein receptor-related protein-5 (LRP5)
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Disturbed Wnt signaling has been implicated in numerous diseases, including type 2 diabetes and the metabolic syndrome. In the present study, we have investigated cross-talk between insulin and Wnt signaling pathways using preadipocytes with and without knockdown of the Wnt co-receptors LRP5 and LRP6 and with and without knock-out of insulin and IGF-1 receptors. We find that Wnt stimulation leads to phosphorylation of insulin signaling key mediators, including Akt, GSK3β, and ERK1/2, although with a lower fold stimulation and slower time course than observed for insulin. These Wnt effects are insulin/IGF-1 receptor-dependent and are lost in insulin/IGF-1 receptor double knock-out cells. Conversely, in LRP5 knockdown preadipocytes, insulin-induced phosphorylation of IRS1, Akt, GSK3β, and ERK1/2 is highly reduced. This effect is specific to insulin, as compared with IGF-1, stimulation and appears to be due to an inducible interaction between LRP5 and the insulin receptor as demonstrated by co-immunoprecipitation. These data demonstrate that Wnt and insulin signaling pathways exhibit cross-talk at multiple levels. Wnt induces phosphorylation of Akt, ERK1/2, and GSK3β, and this is dependent on insulin/IGF-1 receptors. Insulin signaling also involves the Wnt co-receptor LRP5, which has a positive effect on insulin signaling. Thus, altered Wnt and LRP5 activity can serve as modifiers of insulin action and insulin resistance in the pathophysiology of diabetes and metabolic syndrome.
Originalsprog | Engelsk |
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Tidsskrift | The Journal of Biological Chemistry |
Vol/bind | 287 |
Udgave nummer | 15 |
Sider (fra-til) | 12016-26 |
Antal sider | 11 |
ISSN | 0021-9258 |
DOI | |
Status | Udgivet - 6 apr. 2012 |
- 3T3-L1 Cells, Adipocytes, Animals, Gene Expression Regulation, Gene Knockdown Techniques, Glycogen Synthase Kinase 3, Immunoprecipitation, Insulin, Kinetics, Low Density Lipoprotein Receptor-Related Protein-5, Low Density Lipoprotein Receptor-Related Protein-6, MAP Kinase Signaling System, Mice, Phosphorylation, Protein Binding, Proto-Oncogene Proteins c-akt, RNA Interference, Receptor Cross-Talk, Receptor, IGF Type 1, Receptor, Insulin, Wnt Signaling Pathway, Wnt3A Protein, beta Catenin
Forskningsområder
ID: 143328427