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We aimed to define the effects of peroxisomal proliferator-activated receptor γ (PPARγ) and PPARα agonist mono and combination therapy on adipose tissue and skeletal muscle gene expression in relation to insulin sensitivity. We further investigated the role of genetic polymorphisms in PPAR ligand-modulated genes in transcriptional regulation and glucose homeostasis.Genome-wide transcript profiles of subcutaneous adipose and skeletal muscle and metabolic phenotypes were assessed before and after 10 weeks of pioglitazone and fenofibrate mono or combination therapy in 26 patients with impaired glucose tolerance. To establish the functional role of single nucleotide polymorphisms (SNPs) in genes modulated by pioglitazone alone or in combination with fenofibrate, we examined genome-wide association data of continuous glycemic phenotypes from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium study and adipose eQTL data from the Multi Tissue Human Expression Resource study.PPARγ, alone or in combination with PPARα agonists, mediated upregulation of genes involved in the TCA cycle, branched-chain amino acid (BCAA) metabolism, fatty acid metabolism, PPAR signaling, AMPK and cAMP signaling, and insulin signaling pathways, and downregulation of genes in antigen processing and presentation, and immune and inflammatory response in adipose tissue. Remarkably few changes were found in muscle. Strong enrichment of genes involved in propanoate metabolism, fatty acid elongation in the mitochondria, and acetyl-CoA metabolic process were observed only in adipose tissue of the combined pioglitazone and fenofibrate treatment group. After examining Meta-Analyses of Glucose and Insulin-Related Traits Consortium data, SNPs in 22 genes modulated by PPAR ligands were associated with fasting plasma glucose and the expression of 28 transcripts modulated by PPAR ligands was under control of local genetic regulators (cis-eQTLs) in adipose tissue of Multi Tissue Human Expression Resource study twins.We found differences in transcriptional mechanisms that may describe the insulin-sensitizing effects of PPARγ agonist monotherapy or in combination with a PPARα agonist. The regulatory and glucose homeostasis trait-associated SNPs in PPAR agonist-modulated genes are important candidates for future studies that may explain the interindividual variability in response to thiazolidinedione and fenofibrate treatment.