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/EBPα, adiponectin, perilipin, and the adipose-specific fatty acid-binding protein, FABP4/aP2. Since the expression of these proteins lies downstream of PPARγ, we overexpressed PPARγ in Swiss mouse fibroblasts to promote adipocyte differentiation. We show that FoxC2 blocks the ability of PPARγ to induce adipogenic gene expression in response to exposure of the cells to dexamethasone, isobutylmethylxanthine, insulin, and a PPARγ ligand. Interestingly, the expression of aP2 escapes the inhibitory action of FoxC2 under conditions that promote maximum PPARγ activity. In contrast, FoxC2 inhibits the expression of C/EBPα, perilipin, and adiponectin even in the presence of potent PPARγ ligands. Finally, we show that FoxC2 does not affect the ability of PPARγ to bind to or transactivate from a PPARγ response element. These data suggest that FoxC2 blocks adipogenesis by inhibiting the capacity of PPARγ to promote the expression of a subset of adipogenic genes.