Article: article from journal or magazin.
Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes.
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.
Adipose Tissue/drug effects, Adipose Tissue/metabolism, Animals, Diabetes Mellitus, Type 2/blood, Diabetes Mellitus, Type 2/metabolism, Disease Models, Animal, Gene Expression Regulation, Glucose Transporter Type 4, Hepatocytes/drug effects, Hepatocytes/enzymology, Insulin/pharmacology, Insulin Resistance/physiology, Liver/cytology, Liver/drug effects, Mice, Mice, Knockout, Monosaccharide Transport Proteins/deficiency, Monosaccharide Transport Proteins/genetics, Muscle Proteins/deficiency, Muscle Proteins/genetics, Muscles/drug effects, Muscles/metabolism, Obesity/blood, Obesity/metabolism, Oligonucleotide Array Sequence Analysis, Phosphoenolpyruvate Carboxykinase (GTP)/metabolism, Retinol-Binding Proteins/genetics, Retinol-Binding Proteins/metabolism, Retinol-Binding Proteins, Plasma, Signal Transduction/drug effects, Thiazolidinediones/pharmacology
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