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.