Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 290, Issue 32, Pages 19458-19468Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.641332
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Funding
- Science and Technology Development Fund (FDCT) of Macao SAR [FDCT 025/2014/A1, FDCT 088/2014/A2]
- University of Macau [MYRG2015-00037-FHS, MYRG2015-00167-FHS]
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A better understanding of the mechanism and manipulation of the tightly regulated cellular differentiation process of adipogenesis may contribute to a reduction in obesity and diabetes. Multiple transcription factors and signaling pathways are involved in the regulation of adipogenesis. Here, we report that the AMP-activated protein kinase activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) can activate AMPK in preadipocytes and thus increase the expression of GATA3, an anti-adipogenic factor. However, AICAR-increased GATA3 is mediated by the stimulation of Wnt/beta-catenin signaling in preadipocytes. Mechanistically, AICAR-activated AMPK inhibits GSK3 beta through a phosphorylation process that stabilizes beta-catenin. This stabilized beta-catenin then translocates into nucleus where it interacts with T-cell factors (TCF), leading to the increased beta-catenin/TCF transcriptional activity that induces GATA3 expression. In addition, AICAR also relieves the repressing effect of the C-terminal-binding protein (CtBP) co-repressor by diverting CtBP away from the beta-catenin center dot TCF complex at the GATA3 promoter. The anti-adipogenic effect of GATA3 and AICAR is consistently attenuated by the disruption of Wnt/beta-catenin signaling. Furthermore, GATA3 suppresses key adipogenic regulators by binding to the promoters of these regulators, such as the peroxisome proliferator-activated receptor-gamma (PPAR gamma) gene, and the disruption of Wnt/beta-catenin signaling reduces the GATA3 binding at the PPAR gamma promoter. In differentiated adipocytes, GATA3 expression inhibition is facilitated by the down-regulation of beta-catenin levels, the reduction in beta-catenin binding, and the increase in CtBP binding at the GATA3 promoter. Our findings shed light on the molecular mechanism of adipogenesis by suggesting that different regulation pathways and adipogenic regulators collectively modulate adipocyte differentiation through cross-talk.
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