Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes

Qin Yang, Timothy E Graham, Nimesh Mody, Frederic Preitner, Odile D Peroni, Janice M Zabolotny, Ko Kotani, Loredana Quadro, Barbara B Kahn

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1441 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)356-62
Number of pages7
JournalNature
Volume436
Issue number7049
DOIs
Publication statusPublished - 21 Jul 2005

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Keywords

  • Adipose Tissue
  • Animals
  • Diabetes Mellitus, Type 2
  • Disease Models, Animal
  • Gene Expression Regulation
  • Glucose Transporter Type 4
  • Hepatocytes
  • Insulin
  • Insulin Resistance
  • Liver
  • Mice
  • Mice, Knockout
  • Monosaccharide Transport Proteins
  • Muscle Proteins
  • Muscles
  • Obesity
  • Oligonucleotide Array Sequence Analysis
  • Phosphoenolpyruvate Carboxykinase (GTP)
  • Retinol-Binding Proteins
  • Retinol-Binding Proteins, Plasma
  • Signal Transduction
  • Thiazolidinediones

Cite this

Yang, Q., Graham, T. E., Mody, N., Preitner, F., Peroni, O. D., Zabolotny, J. M., Kotani, K., Quadro, L., & Kahn, B. B. (2005). Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature, 436(7049), 356-62. https://doi.org/10.1038/nature03711