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

Research output: Contribution to journalArticle

1392 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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Retinol-Binding Proteins
Type 2 Diabetes Mellitus
Insulin Resistance
Obesity
Serum
rosiglitazone
Insulin
Adipocytes
Fenretinide
Muscles
Phosphoenolpyruvate
Glucose Intolerance
Facilitative Glucose Transport Proteins
Liver
Retinoids
High Fat Diet
Oligonucleotide Array Sequence Analysis
Adipose Tissue
Injections

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., ... 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

Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. / Yang, Qin; Graham, Timothy E; Mody, Nimesh; Preitner, Frederic; Peroni, Odile D; Zabolotny, Janice M; Kotani, Ko; Quadro, Loredana; Kahn, Barbara B.

In: Nature, Vol. 436, No. 7049, 21.07.2005, p. 356-62.

Research output: Contribution to journalArticle

Yang, Q, Graham, TE, Mody, N, Preitner, F, Peroni, OD, Zabolotny, JM, Kotani, K, Quadro, L & Kahn, BB 2005, 'Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes', Nature, vol. 436, no. 7049, pp. 356-62. https://doi.org/10.1038/nature03711
Yang, Qin ; Graham, Timothy E ; Mody, Nimesh ; Preitner, Frederic ; Peroni, Odile D ; Zabolotny, Janice M ; Kotani, Ko ; Quadro, Loredana ; Kahn, Barbara B. / Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. In: Nature. 2005 ; Vol. 436, No. 7049. pp. 356-62.
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AB - 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.

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ER -