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

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 β-catenin in the absence of the LRP6 receptor and with maintained axin and Dickkopf-1 protein expression. PPARγ was repressed and PPARγ ligands could not restore the adipogenic markers or reduce the β-catenin levels. The dedifferentiated adipocytes expressed the myofibroblast marker α-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. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.