Abstract
Several lines of evidence suggest that a functional relationship exists between caveolin-1 and insulin signaling. However, it remains unknown whether caveolin-1 is normally required for proper insulin receptor signaling in vivo. To address this issue, we examined the status of insulin receptor signaling in caveolin-1 (-/-)-deficient (Cav-1 null) mice. Here, we show that Cav-1 null mice placed on a high-fat diet for 9 mo develop postprandial hyperinsulinemia. An insulin tolerance test (ITT) revealed that young Cav-1 null mice on a normal chow diet are significantly unresponsive to insulin, compared with their wild-type counterparts. This insulin resistance is due to a primary defect in adipose tissue, as evidenced by drastically reduced insulin receptor protein levels (>90%), without any changes in insulin receptor mRNA levels. These data suggest that caveolin-1 acts as a molecular chaperone that is necessary for the proper stabilization of the insulin receptor in adipocytes in vivo. In support of this notion, we demonstrate that recombinant expression of caveolin-1 in Cav-1 null mouse embryo fibroblasts rescues insulin receptor protein expression. These data provide evidence that the lean body phenotype observed in the Cav-1 knockout mice is due, at least in part, to a defect in insulin-regulated lipogenesis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells
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Adipose Tissue / metabolism*
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Animals
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Caveolin 1
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Caveolins / genetics*
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Cysteine Endopeptidases / metabolism
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Dietary Fats / pharmacology
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Gene Expression
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Glucose Transporter Type 4
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Humans
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Hyperinsulinism / blood
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Hyperinsulinism / genetics*
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Hypoglycemic Agents / blood
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Hypoglycemic Agents / pharmacology
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Insulin / blood
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Insulin / pharmacology
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Insulin Resistance*
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Mice
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Mice, Knockout
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Monosaccharide Transport Proteins / metabolism
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Multienzyme Complexes / metabolism
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Muscle Proteins*
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Muscle, Skeletal / metabolism
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Phosphorylation / drug effects
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Postprandial Period
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Proteasome Endopeptidase Complex
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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RNA, Messenger / analysis
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Receptor, Insulin / genetics*
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Receptor, Insulin / metabolism
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Recombinant Proteins / genetics
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Signal Transduction / physiology
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Up-Regulation
Substances
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CAV1 protein, human
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Cav1 protein, mouse
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Caveolin 1
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Caveolins
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Dietary Fats
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Glucose Transporter Type 4
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Hypoglycemic Agents
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Insulin
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Monosaccharide Transport Proteins
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Multienzyme Complexes
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Muscle Proteins
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Proto-Oncogene Proteins
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RNA, Messenger
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Recombinant Proteins
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SLC2A4 protein, human
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Slc2a4 protein, mouse
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Receptor, Insulin
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex