Abstract

Thiazolidinediones (TZDs) are insulin-sensitizing drugs and are potent agonists of the nuclear peroxisome proliferator-activated receptor- (PPAR-). Although muscle is the major organ responsible for insulin-stimulated glucose disposal, PPAR- 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-, in mouse skeletal muscle. As early as 4 months of age, mice with targeted disruption of PPAR- 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 80% and was unchanged by 3 weeks of TZD treatment. These effects reveal a crucial role for muscle PPAR- in the maintenance of skeletal muscle insulin action, the etiology of insulin resistance and the action of TZDs.