Journal
BIOCHEMICAL JOURNAL
Volume 376, Issue -, Pages 607-613Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20030426
Keywords
C/EBP beta (CCAAT-enhancer-binding protein); dexamethasone; isobutylmethylxanthine; PPAR gamma (peroxisome-proliferator-activated; receptor) ligand; proteasome
Categories
Funding
- NIDDK NIH HHS [DK58825, DK51585, DK46200] Funding Source: Medline
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The Wnt/beta-catenin signalling pathway appears to operate to maintain the undifferentiated state of preadipocytes by inhibiting adipogenic gene expression. To define the mechanisms regulating suppression of Wnt/beta-catenin signalling, we analysed the catenin expression in response to activation of transcription factors that regulate adipogenesis. The results show an extensive down-regulation of nuclear beta-catenin that occurs during the first few days of differentiation of 3T3-L1 preadipocytes and coincides with the induction of the adipogenic transcription factors, C/EBPP (CCAAT-enhancer-binding protein) and PPARgamma (peroxisome-proliferator-activated receptor). To assess the role of each of these factors in this process, we conditionally overexpressed C/EBPP in Swiss mouse fibroblasts using the TET-off system. Abundant expression of C/EBPP alone had minimal effect on beta-catenin expression, whereas expression of C/EBPP, in the presence of dexamethasone, induced PPARgamma expression and caused a measurable decrease in beta-catenin. In addition, exposure of cells expressing both C/EBP and PPARgamma to a potent PPARgamma ligand resulted in an even greater decrease in beta-catenin by mechanisms that involve the proteasome. Our studies also suggest a reciprocal relationship between PPARgamma activity and beta-catenin expression, since ectopic production of Wnt-1 in preadipocytes blocked the induction of PPARgamma gene expression. Moreover, by suppressing beta-catenin expression, ectopic expression of PPARgamma in Wnt-1-expressing preadipocytes rescued the block in adipogenesis after their exposure to the PPARgamma ligand, troglitarzone.
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