Activation of Canonical Wingless-type MMTV Integration Site Family (Wnt) Signaling in Mature Adipocytes Increases β-Catenin Levels and Leads to Cell Dedifferentiation and Insulin Resistance

Birgit Gustafson,Ulf Smith

doi:10.1074/jbc.m110.102855

Abstract

Canonical Wnt ligands are secreted by several cell types in the adipose tissue. We examined if mature adipocytes can also be target cells and found that canonical Wnt activation by Wnt3a induced a marked dedifferentiation of both 3T3-L1 and human adipocytes. Typical adipogenic markers were reduced while undifferentiated cell markers like Pref-1/Dlk1, Wnt10b, and Gata2 were increased. The cells also became insulin-resistant with impaired upstream insulin signaling and reduced glucose uptake. Wnt3a stabilized beta-catenin in the absence of the LRP6 receptor and with maintained axin and Dickkopf-1 protein expression. PPARgamma was repressed and PPARgamma ligands could not restore the adipogenic markers or reduce the beta-catenin levels. The dedifferentiated adipocytes expressed the myofibroblast marker alpha-smooth muscle actin and were also susceptible to osteogenic transdifferentiation. These results identify a novel pathway in mature adipose cells that is critical for maintaining the normal adipocyte phenotype and insulin sensitivity.

Highlights

The wingless-type MMTV integration site family (Wnt)2 signaling pathway plays a fundamental role during embryogenesis and normal cell and organ development
Active canonical Wnt signaling stabilizes and increases total cellular and nuclear ␤-catenin levels, which repress adipogenesis [4], and inhibition of Wnt signaling is necessary for PPAR␥ induction and preadipocyte differentiation
At present, nothing is known about the ability of Wnt proteins to affect fully differentiated adipocytes, because all focus has been on their importance for precursor cell differentiation

Summary

Introduction

The wingless-type MMTV integration site family (Wnt)2 signaling pathway plays a fundamental role during embryogenesis and normal cell and organ development. We examined if mature adipocytes can be target cells and found that canonical Wnt activation by Wnt3a induced a marked dedifferentiation of both 3T3-L1 and human adipocytes. We find that fully differentiated adipocytes are highly responsive to the canonical Wnt ligand-promoting ␤-catenin stabilization, cell dedifferentiation associated with insulin resistance, and ability to undergo transdifferentiation.

Results

Conclusion