FOXO1 Transrepresses Peroxisome Proliferator-activated Receptor γ Transactivation, Coordinating an Insulin-induced Feed-forward Response in Adipocytes

The transcriptional factor FoxO1 plays an important role in metabolic homeostasis. Herein we identify a novel transrepressional function that converts FoxO1 from an activator of transcription to a promoter-specific repressor of peroxisome proliferator-activated receptor gamma (PPAR gamma) target genes that regulate adipocyte biology. FoxO1 transrepresses PPAR gamma via direct protein-protein interactions; it is recruited to PPAR response elements (PPRE) on PPAR gamma target genes by PPAR gamma bound to PPRE and interferes with promoter DNA occupancy of the receptor. The FoxO1 transrepressional function, which is independent and dissectible from the transactivational effects, does not require a functional FoxO1 DNA binding domain, but dose require an evolutionally conserved 31 amino acids LXXLL-containing domain. Insulin induces FoxO1 phosphorylation and nuclear exportation, which prevents FoxO1-PPAR gamma interactions and rescues transrepression. Adipocytes from insulin resistant mice show reduced phosphorylation and increased nuclear accumulation of FoxO1, which is coupled to lowered expression of endogenous PPAR gamma target genes. Thus the innate FoxO1 transrepression function enables insulin to augment PPAR gamma activity, which in turn leads to insulin sensitization, and this feed-forward cycle represents positive reinforcing connections between insulin and PPAR gamma signaling.