title: Wnt/β-Catenin Mediates AICAR Effect to Increase GATA3 Expression and Inhibit Adipogenesis.
abstract: 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/β-catenin signaling in preadipocytes. Mechanistically, AICAR-activated AMPK inhibits GSK3β through a phosphorylation process that stabilizes β-catenin. This stabilized β-catenin then translocates into nucleus where it interacts with T-cell factors (TCF), leading to the increased β-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 β-catenin·TCF complex at the GATA3 promoter. The anti-adipogenic effect of GATA3 and AICAR is consistently attenuated by the disruption of Wnt/β-catenin signaling. Furthermore, GATA3 suppresses key adipogenic regulators by binding to the promoters of these regulators, such as the peroxisome proliferator-activated receptor-γ (PPARγ) gene, and the disruption of Wnt/β-catenin signaling reduces the GATA3 binding at the PPARγ promoter. In differentiated adipocytes, GATA3 expression inhibition is facilitated by the down-regulation of β-catenin levels, the reduction in β-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.
authors.affiliation: From the Metabolomics Core, Faculty of Health Sciences, University of Macau, Macau SAR (Special Administrative Region), China and.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: the Faculty of Health Sciences, University of Macau, Macau SAR, China lijundi@umac.mo.
authors.forename: Li-jun
authors.initials: LJ
authors.lastname: Di
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics; D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D012265:Ribonucleotides / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D012265:Ribonucleotides; D051176:beta Catenin; D000620:Aminoimidazole Carboxamide; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide
keywords: AMP-activated kinase (AMPK); CtBP; GATA transcription factor; GATA3; Wnt pathway; adipogenesis; glycogen synthase kinase 3 (GSK3); β-catenin