Cited by 2,086Adipokines, Inflammation, and Metabolic DiseasesAdipose Tissue and MetabolismPeroxisome Proliferator-Activated Receptors

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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.·2005·Nature

DOI 10.1038/nature03711

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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.

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Authors: Yang, Q., Graham, T. E., Mody, N., Preitner, F., Peroni, O. D., Zabolotny, J. M., Kotani, K., Quadro, L., & Kahn, B. B.
Affiliations: Beth Israel Deaconess Medical Center (US)
Columbia University (US)
Corresponding author: Kahn, Barbara B.
ORCID: Yang, Qin
Mody, Nimesh
Quadro, Loredana
Kahn, Barbara B.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2005-07
Volume: 436
Issue: 7049
Pages: 356-362
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature03711
OpenAlex: W2092136583
Cited by: 2,086
References: 50
Citations by year: 2026: 43 · 2025: 50 · 2024: 80 · 2023: 53 · 2022: 85 · 2021: 86 · 2020: 95 · 2019: 69 · 2018: 76 · 2017: 91 · 2016: 88 · 2015: 120 · 2014: 115 · 2013: 124 · 2012: 135
FWCI: 89.83
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Institute of Diabetes and Digestive and Kidney Diseases (R01DK043051)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords: retinol-binding protein 4, insulin resistance, type 2 diabetes, obesity, GLUT4, adipose tissue, rosiglitazone, fenretinide, phosphoenolpyruvate carboxykinase, hepatic gluconeogenesis, impaired glucose tolerance
MeSH terms: Rosiglitazone, Adipose Tissue, Animals, Diabetes Mellitus, Type 2, Disease Models, Animal, Gene Expression Regulation, Insulin, Insulin Resistance, Liver, Monosaccharide Transport Proteins, Muscle Proteins, Muscles, Obesity, Phosphoenolpyruvate Carboxykinase (GTP), Retinol-Binding Proteins, Signal Transduction, Mice, Knockout, Oligonucleotide Array Sequence Analysis, Hepatocytes, Thiazolidinediones, Glucose Transporter Type 4, Mice, Retinol-Binding Proteins, Plasma

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

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