Signal Transduction
Cross-talk between Insulin and Wnt Signaling in Preadipocytes: ROLE OF WNT CO-RECEPTOR LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN-5 (LRP5)*

https://doi.org/10.1074/jbc.M111.337048Get rights and content
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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.

Adipogenesis
Insulin
Insulin-like Growth Factor (IGF)
Signal Transduction
Wnt Signaling
LDL Receptor-related Protein-5 (LRP-5)
Insulin Action
Signaling Cross-talk

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*

This work was supported, in whole or in part, by National Institutes of Health Grants DK31036, DK33201, and DK55545.

This article contains supplemental Figs. S1–S5.

1

Supported by a Novo Nordisk STAR International postdoctoral fellowship.