Re-expression of GATA2 Cooperates with Peroxisome Proliferator-activated Receptor-γ Depletion to Revert the Adipocyte Phenotype

Nuclear peroxisome proliferator-activated receptor-γ (PPARγ) is required for adipocyte differentiation, but its role in mature adipocytes is less clear. Here, we report that knockdown of PPARγ expression in 3T3-L1 adipocytes returned the expression of most adipocyte genes to preadipocyte levels. Consistently, down-regulated but not up-regulated genes showed strong enrichment of PPARγ binding. Surprisingly, not all adipocyte genes were reversed, and the adipocyte morphology was maintained for an extended period after PPARγ depletion. To explain this, we focused on transcriptional regulators whose adipogenic regulation was not reversed upon PPARγ depletion. We identified GATA2, a transcription factor whose down-regulation early in adipogenesis is required for preadipocyte differentiation and whose levels remain low after PPARγ knockdown. Forced expression of GATA2 in mature adipocytes complemented PPARγ depletion and impaired adipocyte functionality with a more preadipocyte-like gene expression profile. Ectopic expression of GATA2 in adipose tissue in vivo had a similar effect on adipogenic gene expression. These results suggest that PPARγ-independent down-regulation of GATA2 prevents reversion of mature adipocytes after PPARγ depletion.