Abstract
In obesity and type 2 diabetes, expression of the GLUT4 glucose transporter is decreased selectively in adipocytes. Adipose-specific Glut4 (also known as Slc2a4) knockout (adipose-Glut4(-/-)) mice show insulin resistance secondarily in muscle and liver. Here we show, using DNA arrays, that expression of retinol binding protein-4 (RBP4) is elevated in adipose tissue of adipose-Glut4(-/-) mice. We show that serum RBP4 levels are elevated in insulin-resistant mice and humans with obesity and type 2 diabetes. RBP4 levels are normalized by rosiglitazone, an insulin-sensitizing drug. Transgenic overexpression of human RBP4 or injection of recombinant RBP4 in normal mice causes insulin resistance. Conversely, genetic deletion of Rbp4 enhances insulin sensitivity. Fenretinide, a synthetic retinoid that increases urinary excretion of RBP4, normalizes serum RBP4 levels and improves insulin resistance and glucose intolerance in mice with obesity induced by a high-fat diet. Increasing serum RBP4 induces hepatic expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and impairs insulin signalling in muscle. Thus, RBP4 is an adipocyte-derived 'signal' that may contribute to the pathogenesis of type 2 diabetes. Lowering RBP4 could be a new strategy for treating type 2 diabetes.
Publication types
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Research Support, N.I.H., Extramural
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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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Adipose Tissue / drug effects
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Adipose Tissue / metabolism
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Animals
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Diabetes Mellitus, Type 2 / blood*
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Diabetes Mellitus, Type 2 / metabolism
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Disease Models, Animal
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Gene Expression Regulation
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Glucose Transporter Type 4
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Hepatocytes / drug effects
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Hepatocytes / enzymology
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Hepatocytes / metabolism
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Insulin / pharmacology
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Insulin Resistance / physiology*
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Liver / cytology
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Liver / drug effects
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Liver / enzymology
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Mice
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Mice, Knockout
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Monosaccharide Transport Proteins / deficiency
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Monosaccharide Transport Proteins / genetics
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Monosaccharide Transport Proteins / metabolism
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Muscle Proteins / deficiency
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Muscle Proteins / genetics
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Muscle Proteins / metabolism
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Muscles / drug effects
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Muscles / metabolism
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Obesity / blood*
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Obesity / metabolism
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Oligonucleotide Array Sequence Analysis
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Phosphoenolpyruvate Carboxykinase (GTP) / metabolism
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Retinol-Binding Proteins / genetics
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Retinol-Binding Proteins / metabolism*
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Retinol-Binding Proteins, Plasma
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Rosiglitazone
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Signal Transduction / drug effects
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Thiazolidinediones / pharmacology
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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Rbp4 protein, mouse
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Retinol-Binding Proteins
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Retinol-Binding Proteins, Plasma
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Slc2a4 protein, mouse
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Thiazolidinediones
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Rosiglitazone
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Phosphoenolpyruvate Carboxykinase (GTP)