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 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.
Hevener
Andrea L
AL
Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California 92093, USA.
He
Weimin
W
Barak
Yaacov
Y
Le
Jamie
J
Bandyopadhyay
Gautam
G
Olson
Peter
P
Wilkes
Jason
J
Evans
Ronald M
RM
Olefsky
Jerrold
J
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015870:Gene Expression / Q000187:drug effects; D015309:Glucose Clamp Technique; D051275:Glucose Transporter Type 4; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000172:deficiency* / Q000235:genetics*; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists / Q000172:deficiency* / Q000235:genetics*
D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C495693:Slc2a4 protein, mouse; D045162:Thiazolidinediones; D014157:Transcription Factors; C089946:2,4-thiazolidinedione