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Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes
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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“The secretion of these proinflammatory cytokines and chemokines, as well as the secretion of other adipokines like retinol binding protein 4 (RBP4) 141, 142, is now well admitted to contribute to the onset of the physiological alterations accompanying obesity 12.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [141]
Citations
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Metadata
- 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.
- Venue
- Nature
- Published
- 2005-07
- Volume
- 436
- Issue
- 7049
- Pages
- 356-362
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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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