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J. Biol. Chem. 287 (15): 12016-12026

© 2012 by The American Society for Biochemistry and Molecular Biology, Inc.


Background: Wnt signaling blocks adipocyte development and is implicated in diabetes and the metabolic syndrome.

Results: Wnt stimulates insulin mediators via an insulin/IGF-1 receptor-dependent process; conversely, Wnt co-receptor LRP5 is essential to normal insulin signaling in preadipocytes.

Conclusion: Insulin and Wnt signaling pathways interact and are both dependent on LRP5.

Significance: Altered Wnt/LRP5 activity can play a role in obesity and insulin resistance.


Cross-talk between Insulin and Wnt Signaling in Preadipocytes

ROLE OF WNT CO-RECEPTOR LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN-5 (LRP5)*Formula

Jane Palsgaard{ddagger}1, Brice Emanuelli{ddagger}, Jonathon N. Winnay{ddagger}, Grzegorz Sumara§, Gerard Karsenty§, , and C. Ronald Kahn{ddagger}2

From the {ddagger}Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215 and
the §Department of Genetics and Development, Columbia University Medical School, New York, New York 10032

ABSTRACT Back to Top

Abstract: 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.


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

Received for publication December 22, 2011. Revision received February 13, 2012.

FOOTNOTES Back to Top

1 Supported by a Novo Nordisk STAR International postdoctoral fellowship.

2 To whom correspondence should be addressed: Joslin Diabetes Center, One Joslin Pl., Boston, MA 02215. Tel.: 617-309-2635; Fax: 617-309-2487; E-mail: c.ronald.kahn{at}joslin.harvard.edu.


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