Peroxisome proliferator-activated receptor gamma (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 multi-tissue gene expression profiles of lean and insulin resistant, obese Zucker rats untreated or treated with one of four PPARγ ligands (pioglitazone, rosiglitazone, troglitazone, and AG035029). We analyzed the transcriptional profiles of adipose tissue, skeletal muscle, and liver from the rats and determined whether ligand insulin-sensitizing potency was related to ligand-induced alteration of functional pathways. Ligand treatments improved insulin sensitivity in obese rats, albeit to varying degrees. Adipose tissue profiles revealed ligand-selective modulation of inflammatory and branched chain amino acid (BCAA) metabolic pathways which correlated with ligand-specific insulin-sensitizing potency. Skeletal muscle profiles showed that insulin resistance was associated with increased expression of adipocyte and slow-twitch fiber markers, a pattern that was augmented similarly in all the ligand-treated groups. 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-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-induced functional pathway changes were detected in adipose tissue, skeletal muscle and liver profiles but were not related to degree of insulin sensitization.
- thiazolidinedione (TZD)
- insulin resistance
- branched chain amino acids (BCAA)
- adipose tissue inflammation
- Copyright © 2010, American Journal of Physiology - Endocrinology and Metabolism