Serum Retinol Binding Protein 4 Contributes to Insulin Resistance in Obesity and Type 2 Diabetes

Nature. 2005 Jul 21;436(7049):356-62. doi: 10.1038/nature03711.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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
  • Hepatocytes / metabolism
  • Insulin / pharmacology
  • Insulin Resistance / physiology*
  • Liver / cytology
  • Liver / drug effects
  • Liver / enzymology
  • Mice
  • Mice, Knockout
  • Monosaccharide Transport Proteins / deficiency
  • Monosaccharide Transport Proteins / genetics
  • Monosaccharide Transport Proteins / metabolism
  • Muscle Proteins / deficiency
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • 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
  • Rosiglitazone
  • Signal Transduction / drug effects
  • Thiazolidinediones / pharmacology

Substances

  • Glucose Transporter Type 4
  • Insulin
  • Monosaccharide Transport Proteins
  • Muscle Proteins
  • Rbp4 protein, mouse
  • Retinol-Binding Proteins
  • Retinol-Binding Proteins, Plasma
  • Slc2a4 protein, mouse
  • Thiazolidinediones
  • Rosiglitazone
  • Phosphoenolpyruvate Carboxykinase (GTP)