ARTD1-induced poly-ADP-ribose formation enhances PPAR gamma ligand binding and co-factor exchange

PPAR gamma-dependent gene expression during adipogenesis is facilitated by ADP-ribosyltransferase D-type 1 (ARTD1; PARP1)-catalyzed poly-ADP-ribose (PAR) formation. Adipogenesis is accompanied by a dynamic modulation of the chromatin landscape at PPAR gamma target genes by ligand-dependent co-factor exchange. However, how endogenous PPAR gamma ligands, which have a low affinity for the receptor and are present at low levels in the cell, can induce sufficient co-factor exchange is unknown. Moreover, the significance of PAR formation in PPAR gamma-regulated adipose tissue function is also unknown. Here, we show that inhibition of PAR formation in mice on a high-fat diet reduces weight gain and cell size of adipocytes, as well as PPAR gamma target gene expression in white adipose tissue. Mechanistically, topoisomerase II activity induces ARTD1 recruitment to PPAR gamma target genes, and ARTD1 automodification enhances ligand binding to PPAR gamma, thus promoting sufficient transcriptional co-factor exchange in adipocytes. Thus, ARTD1-mediated PAR formation during adipogenesis is necessary to adequately convey the low signal of endogenous PPAR gamma ligand to effective gene expression. These results uncover a new regulatory mechanism of ARTD1- induced ADP-ribosylation and highlight its importance for nuclear factor-regulated gene expression.