The forkhead transcription factor FoxC2 inhibits white adipocyte differentiation.
In this study, we show that expression of FoxC2 blocks the capacity of 3T3-L1 preadipocytes to undergo adipogenesis in the presence of dexamethasone, isobutylmethylxanthine, and insulin. This block is characterized by an extensive decrease in the expression of proteins associated with the function of the mature fat cell, most notably C/EBPalpha, adiponectin, perilipin, and the adipose-specific fatty acid-binding protein, FABP4/aP2. Since the expression of these proteins lies downstream of PPARgamma, we overexpressed PPARgamma in Swiss mouse fibroblasts to promote adipocyte differentiation. We show that FoxC2 blocks the ability of PPARgamma to induce adipogenic gene expression in response to exposure of the cells to dexamethasone, isobutylmethylxanthine, insulin, and a PPARgamma ligand. Interestingly, the expression of aP2 escapes the inhibitory action of FoxC2 under conditions that promote maximum PPARgamma activity. In contrast, FoxC2 inhibits the expression of C/EBPalpha, perilipin, and adiponectin even in the presence of potent PPARgamma ligands. Finally, we show that FoxC2 does not affect the ability of PPARgamma to bind to or transactivate from a PPARgamma response element. These data suggest that FoxC2 blocks adipogenesis by inhibiting the capacity of PPARgamma to promote the expression of a subset of adipogenic genes.
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Kathryn E
KE
Davis
Marthe
M
Moldes
Stephen R
SR
Farmer
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D052242:Adiponectin; D000818:Animals; D001391:Azo Compounds / Q000494:pharmacology; D015153:Blotting, Western; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D050556:Fatty Acid-Binding Proteins; D005347:Fibroblasts / Q000378:metabolism; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism; D000070778:Perilipin-1; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D020218:Response Elements; D045162:Thiazolidinediones / Q000494:pharmacology; D013997:Time Factors; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D000077288:Troglitazone
D052242:Adiponectin; D001391:Azo Compounds; D022763:CCAAT-Enhancer-Binding Protein-alpha; D002352:Carrier Proteins; D002839:Chromans; D004268:DNA-Binding Proteins; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D051858:Forkhead Transcription Factors; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D047495:PPAR gamma; D000070778:Perilipin-1; D010726:Phosphodiesterase Inhibitors; D010750:Phosphoproteins; D045162:Thiazolidinediones; D050656:Transcription Factor AP-2; D014157:Transcription Factors; C082078:mesenchyme fork head 1 protein; D003907:Dexamethasone; D008156:Luciferases; C011049:oil red O; D000077288:Troglitazone; D015056:1-Methyl-3-isobutylxanthine