Novel Transcriptome Profiling Analyses Demonstrate that Selective PPARg Modulators Display Attenuated and Selective Gene Regulatory Activity in Comparison with PPARg Full Agonists . Mus musculus

We conducted extensive transcriptome profiling studies to characterize 70 SPPARgMs and seven PPARg full agonists in 3T3-L1 adipocytes, and a subset of these ligands in adipose tissue of diabetic db/db mice. In both cases, the SPPARgMs generated attenuated gene regulatory responses, and their gene expression signatures were more enriched in metabolic pathways that are likely to mediate anti-diabetic efficacy than those of PPARg full agonists. More importantly, our profiling results demonstrated that in both 3T3-L1 adipocytes and db/db mice, SPPARgMs regulate the expression of anti-diabetic efficacy-associated genes to a greater extent than that of adverse effect-associated genes, while PPARg full agonists regulate both gene sets proportionally. Overall design: We conducted 10 independent batches of profiling experiments. Within each batch, drug treatment and pool of vehicle controls were hybridized to the Agilent two channel microarray. Generally 2-3 biological replicates for each condition.