Cell-state dependent regulation of PPAR _γ signaling by ZBTB9 in adipocytes

Adipocytes play a critical role in metabolic homeostasis. Peroxisome proliferator-activated receptor- _γ (PPAR _γ ) is a nuclear hormone receptor that is a master regulator of adipocyte differentiation and function. ZBTB9 was predicted to interact with PPAR _γ based on large-scale protein interaction experiments. In addition, GWAS studies in the type 2 diabetes (T2D) Knowledge Portal revealed associations between Z btb9 and both BMI and T2D risk. Here we show that ZBTB9 positively regulates PPAR _γ activity in mature adipocytes. Surprisingly Z btb9 knockdown (KD) also increased adipogenesis in 3T3-L1 cells and human preadipocytes. E2F activity was increased and E2F downstream target genes were upregulated in Zbtb9 -KD preadipocytes. Accordingly, RB phosphorylation, which regulates E2F activity, was enhanced in Zbtb9 -KD preadipocytes. Critically, an E2F1 inhibitor blocked the effects of Zbtb9 deficiency on adipogenic gene expression and lipid accumulation. Collectively, these results demonstrate that Zbtb9 inhibits adipogenesis as a negative regulator of Pparg expression via altered RB-E2F1 signaling. Our findings reveal complex cell-state dependent roles of ZBTB9 in adipocytes, identifying a new molecule that regulates adipogenesis and adipocyte biology as both a positive and negative regulator of PPAR _γ signaling depending on the cellular context, and thus may be important in the pathogenesis and treatment of obesity and T2D.