Acute genome-wide effects of rosiglitazone on PPARγ transcriptional networks in adipocytes

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) is a master regulator of adipocyte differentiation, and genome-wide studies indicate that it is involved in the induction of most adipocyte genes. Here we report, for the first time, the acute effects of the synthetic PPARγagonist rosiglitazone on the transcriptional network of PPARγin adipocytes. Treatment with rosiglitazone for 1 hour leads to acute transcriptional activation as well as repression of a number of genes as determined by genome-wide RNA polymerase II occupancy. Unlike what has been shown for many other nuclear receptors, agonist treatment does not lead to major changes in the occurrence of PPARγbinding sites. However, rosiglitazone promotes PPARγoccupancy at many preexisting sites, and this is paralleled by increased occupancy of the mediator subunit MED1. The increase in PPARγ and MED1 binding is correlated with an increase in transcription of nearby genes, indicating that rosiglitazone, in addition to activating the receptor, also promotes its association with DNA, and that this is causally linked to recruitment of mediator and activation of genes. Notably, both rosiglitazone-activated and -repressed genes are induced during adipogenesis. However, rosiglitazone- activated genes are markedly more associated with PPARγthan repressed genes and are highly dependent on PPARγfor expression in adipocytes. By contrast, repressed genes are associated with the other key adipocyte transcription factor CCAAT-enhancer binding proteinα (C/EBPα), and their expression is more dependent on C/EBPα. This suggests that the relative occupancies of PPARγand C/EBPα are critical for whether genes will be induced or repressed by PPARγagonist. © 2013 by The Endocrine Society.