Peroxisome proliferator-activated receptor g (PPARg) agonists, in- cluding the glitazone class of drugs, are insulin sensitizers that reduce glucose and lipid levels in patients with type 2 diabetes mellitus. To more fully understand the molecular mechanisms underlying their therapeutic actions, we have characterized the effects of the potent, tyrosine-based PPARg ligand GW1929 on serum glucose and lipid parameters and gene expression in Zucker diabetic fatty rats. In time-course studies, GW1929 treatment decreased circulating FFA levels before reducing glucose and triglyceride levels. We used a com- prehensive and unbiased messenger RNA profiling technique to iden- tify genes regulated either directly or indirectly by PPARg in epidi- dymal white adipose tissue, interscapular brown adipose tissue, liver, and soleus skeletal muscle. PPARg activation stimulated the expres- sion of a large number of genes involved in lipogenesis and fatty acid metabolism in both white adipose tissue and brown adipose tissue. In muscle, PPARg agonist treatment decreased the expression of pyru- vate dehydrogenase kinase 4, which represses oxidative glucose me- tabolism, and also decreased the expression of genes involved in fatty acid transport and oxidation. These changes suggest a molecular basis for PPARg-mediated increases in glucose utilization in muscle. In liver, PPARg activation coordinately decreased the expression of genes involved in gluconeogenesis. We conclude from these studies that the antidiabetic actions of PPARg agonists are probably the consequence of 1) their effects on FFA levels, and 2), their coordinate effects on gene expression in multiple insulin-sensitive tissues. (En- docrinology 142: 1269 -1277, 2001)