TY - JOUR

T1 - Cross-talk between insulin and Wnt signaling in preadipocytes

T2 - role of Wnt co-receptor low density lipoprotein receptor-related protein-5 (LRP5)

AU - Palsgaard, Jane

AU - Emanuelli, Brice

AU - Winnay, Jonathon N

AU - Sumara, Grzegorz

AU - Karsenty, Gerard

AU - Kahn, C Ronald

PY - 2012/4/6

Y1 - 2012/4/6

N2 - 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.

AB - 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.

KW - 3T3-L1 Cells

KW - Adipocytes

KW - Animals

KW - Gene Expression Regulation

KW - Gene Knockdown Techniques

KW - Glycogen Synthase Kinase 3

KW - Immunoprecipitation

KW - Insulin

KW - Kinetics

KW - Low Density Lipoprotein Receptor-Related Protein-5

KW - Low Density Lipoprotein Receptor-Related Protein-6

KW - MAP Kinase Signaling System

KW - Mice

KW - Phosphorylation

KW - Protein Binding

KW - Proto-Oncogene Proteins c-akt

KW - RNA Interference

KW - Receptor Cross-Talk

KW - Receptor, IGF Type 1

KW - Receptor, Insulin

KW - Wnt Signaling Pathway

KW - Wnt3A Protein

KW - beta Catenin

U2 - 10.1074/jbc.M111.337048

DO - 10.1074/jbc.M111.337048

M3 - Journal article

C2 - 22337886

VL - 287

SP - 12016

EP - 12026

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 15

ER -