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J. Biol. Chem., Vol. 279, Issue 43, 45020-45027, October 22, 2004

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Regulating the Balance between Peroxisome Proliferator-activated Receptor and -Catenin Signaling during Adipogenesis

A GLYCOGEN SYNTHASE KINASE 3 PHOSPHORYLATION-DEFECTIVE MUTANT OF -CATENIN INHIBITS EXPRESSION OF A SUBSET OF ADIPOGENIC GENES^*

Jiajian Liu and Stephen R. Farmer

From the Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118

The differentiation of preadipocytes into adipocytes requires the suppression of canonical Wnt signaling, which appears to involve a peroxisome proliferator-activated receptor (PPAR)-associated targeting of -catenin to the proteasome. In fact, sustained activation of -catenin by expression of Wnt1 or Wnt 10b in preadipocytes blocks adipogenesis by inhibiting PPAR-associated gene expression. In this report, we investigated the mechanisms regulating the balance between -catenin and PPAR signaling that determines whether mouse fibroblasts differentiate into adipocytes. Specifically, we show that activation of PPAR by exposure of Swiss mouse fibroblasts to troglitazone stimulates the degradation of -catenin, which depends on glycogen synthase kinase (GSK) 3 activity. Mutation of serine 37 (a target of GSK3) to an alanine renders -catenin resistant to the degradatory action of PPAR. Ectopic expression of the GSK3 phosphorylation-defective S37A--catenin in Swiss mouse fibroblasts expressing PPAR stimulates the canonical Wnt signaling pathway without blocking their troglitazone-dependent differentiation into lipid-laden cells. Analysis of protein expression in these cells, however, shows that S37A--catenin inhibits a select set of adipogenic genes because adiponectin expression is completely blocked, but FABP4/aP2 expression is unaffected. Furthermore, the mutant -catenin appears to have no affect on the ability of PPAR to bind to or transactivate a PPAR response element. The S37A--catenin-associated inhibition of adiponectin expression coincides with an extensive decrease in the abundance of C/EBP in the nuclei of the differentiated mouse fibroblasts. Taken together, these data suggest that GSK is a key regulator of the balance between -catenin and PPAR activity and that activation of canonical Wnt signaling downstream of PPAR blocks expression of a select subset of adipogenic genes.

Received for publication, June 23, 2004 , and in revised form, August 10, 2004.

^* This work was supported by United States Public Health Service Grants DK51586 and DK58825. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Biochemistry, Boston University School of Medicine, 715 Albany St., Boston, MA 02118. Tel.: 617-638-4186; Fax: 617-638-5339; E-mail: farmer{at}biochem.bumc.bu.edu.

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