Comprehensive messenger ribonucleic acid profiling reveals that peroxisomeproliferator-activated receptor gamma activation has coordinate effects ongene expression in multiple insulin-sensitive tissues

Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists, inc luding the glitazone class of drugs, are insulin sensitizers that reduce gl ucose and lipid levels in patients with type 2 diabetes mellitus. To more f ully understand the molecular mechanisms underlying their therapeutic actio ns, we have characterized the effects of the potent, tyrosine-based PPAR ga mma ligand GW1929 on serum glucose and lipid parameters and gene expression in Zucker diabetic fatty rats. In time-course studies, GW1929 treatment de creased circulating FFA levels before reducing glucose and triglyceride lev els. We used a comprehensive and unbiased messenger RNA profiling technique to identify genes regulated either directly or indirectly by PPAR gamma in epididymal white adipose tissue, interscapular brown adipose tissue, liver , and soleus skeletal muscle. PPAR gamma activation stimulated the expressi on of a large number of genes involved in lipogenesis and fatty acid metabo lism in both white adipose tissue and brown adipose tissue. In muscle, PPAR gamma agonist treatment decreased the expression of pyruvate dehydrogenase kinase 4, which represses oxidative glucose metabolism, and also decreased the expression of genes involved in fatty acid transport and oxidation. Th ese changes suggest a molecular basis for PPAR gamma -mediated increases in glucose utilization in muscle. In liver, PPAR gamma activation coordinatel y decreased the expression of genes involved in gluconeogenesis. We conclud e from these studies that the antidiabetic actions of PPAR gamma agonists a re probably the consequence of ii their effects on FFA levels, and 2), thei r coordinate effects on gene expression in multiple insulin-sensitive tissu es.