Muscle-specific Pparg deletion causes insulin resistance.

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Publication Date



Animals, Gene-Expression, Glucose-Clamp-Technique, Insulin, Insulin-Resistance, Liver, Mice-Inbred-C57BL, Mice-Knockout, Mice-Transgenic, Monosaccharide-Transport-Proteins, Muscle-Skeletal, RNA-Messenger, Receptors-Cytoplasmic-and-Nuclear, Signal-Transduction, Thiazolidinediones, Transcription-Factors

JAX Source

Nat Med 2003 Dec; 9(12):1491-7.


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 approximately 80% 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.