Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats

Peroxisome proliferator-activated receptor-γ (PPARγ) ligands, including the insulin-sensitizing thiazolidinedione drugs, transcriptionally regulate hundreds of genes. Little is known about the relationship between PPARγ ligand-specific modulation of cellular mechanisms and insulin sensitization. We characterized the insulin sensitivity and multitissue gene expression profiles of lean and insulin-resistant, obese Zucker rats untreated or treated with one of four PPARγ ligands (pioglitazone, rosiglitazone, troglitazone, and AG-035029). We analyzed the transcriptional profiles of adipose tissue, skeletal muscle, and liver from the rats and determined whether ligand treatment insulin-sensitizing potency was related to ligand treatment-induced alteration of functional pathways. Ligand treatments improved insulin sensitivity in obese rats to varying degrees. Adipose tissue profiles revealed ligand treatment-selective modulation of inflammatory and branched-chain amino acid (BCAA) metabolic pathways, which correlated with ligand treatment-specific insulin-sensitizing potency. Skeletal muscle profiles showed that obese rats exhibited elevated expression of adipocyte and slow-twitch fiber markers, which further increased after ligand treatment, but the magnitude of the treatment-induced changes was not correlated with insulin sensitization. Although PPARγ ligand treatments heterogeneously improved dysregulated expression of cholesterol and fatty acid biosynthetic pathways in obese rat liver, these alterations were not correlated with ligand insulin-sensitizing potency. PPARγ ligand treatment-specific insulin-sensitizing potency correlated with modulation of adipose tissue inflammatory and BCAA metabolic pathways, suggesting a functional relationship between these pathways and whole body insulin sensitivity. Other PPARγ ligand treatment-induced functional pathway changes were detected in adipose tissue, skeletal muscle, and liver profiles but were not related to degree of insulin sensitization.