Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adipose Tissue / drug effects
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Adipose Tissue / metabolism
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Animals
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Gene Expression / drug effects
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Glucose Clamp Technique
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Glucose Transporter Type 4
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Insulin / metabolism
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Insulin Resistance / genetics
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Insulin Resistance / physiology*
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Liver / drug effects
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Liver / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Monosaccharide Transport Proteins / metabolism
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Muscle Proteins*
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Muscle, Skeletal / drug effects
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Muscle, Skeletal / metabolism*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Cytoplasmic and Nuclear / agonists
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Receptors, Cytoplasmic and Nuclear / deficiency*
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Receptors, Cytoplasmic and Nuclear / genetics*
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Signal Transduction
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Thiazolidinediones / pharmacology
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Transcription Factors / agonists
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Transcription Factors / deficiency*
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Transcription Factors / genetics*
Substances
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Glucose Transporter Type 4
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Insulin
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Monosaccharide Transport Proteins
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Muscle Proteins
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RNA, Messenger
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Receptors, Cytoplasmic and Nuclear
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Slc2a4 protein, mouse
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Thiazolidinediones
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Transcription Factors
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2,4-thiazolidinedione