Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes
Copyright policy )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.
- Beth Israel Deaconess Medical Center United States
- Harvard University United States
Mice, Knockout, Glucose Transporter Type 4, Monosaccharide Transport Proteins, Muscles, Muscle Proteins, Retinol-Binding Proteins, Disease Models, Animal, Mice, Adipose Tissue, Diabetes Mellitus, Type 2, Gene Expression Regulation, Liver, Hepatocytes, Animals, Insulin, Phosphoenolpyruvate Carboxykinase (GTP), Obesity, Insulin Resistance, Retinol-Binding Proteins, Plasma, Oligonucleotide Array Sequence Analysis
Mice, Knockout, Glucose Transporter Type 4, Monosaccharide Transport Proteins, Muscles, Muscle Proteins, Retinol-Binding Proteins, Disease Models, Animal, Mice, Adipose Tissue, Diabetes Mellitus, Type 2, Gene Expression Regulation, Liver, Hepatocytes, Animals, Insulin, Phosphoenolpyruvate Carboxykinase (GTP), Obesity, Insulin Resistance, Retinol-Binding Proteins, Plasma, Oligonucleotide Array Sequence Analysis
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