Muscle-specific Pparg deletion causes insulin resistance

Thiazolidinediones (TZDs) are insulin- sensitizing drugs and are potent agonists of the nuclear peroxisome proliferator- activated receptor-gamma (PPAR-gamma). Although muscle is the major organ responsible for insulin- stimulated glucose disposal, PPAR-gamma is more highly expressed in adipose tissue than in muscle. To address this issue, we used the Cre- loxP system to knock out Pparg, the gene encoding PPAR-gamma, in mouse skeletal muscle. As early as 4 months of age, mice with targeted disruption of PPAR-gamma in muscle showed glucose intolerance and progressive insulin resistance. Using the hyperinsulinemic- euglycemic clamp technique, the in vivo insulin- stimulated glucose disposal rate (IS- GDR) was reduced by similar to80% and was unchanged by 3 weeks of TZD treatment. These effects reveal a crucial role for muscle PPAR-gamma in the maintenance of skeletal muscle insulin action, the etiology of insulin resistance and the action of TZDs.