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

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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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Figure 1: Elevation of RBP4 in insulin-resistant mouse models.
Figure 2: Rosiglitazone treatment decreases RBP4 levels in adipose- Glut4 -/- mice.
Figure 3: Elevated serum RBP4 causes insulin resistance.
Figure 4: Lowering serum RBP4 levels improves insulin action.
Figure 5: Effects of RBP4 on insulin signalling, hepatic PEPCK expression and hepatocyte glucose production.

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Acknowledgements

We are indebted to W. S. Blaner and M. Gottesman for RBP4-overexpressing and Rbp4 knockout mice; T. Ciaraldi and R. R. Henry for human serum samples and metabolic data; Takeda Pharmaceutical Company Limited for recombinant mouse RBP4 and M. Fujisawa for sharing unpublished data; the BIDMC DNA Array Facility for assisting with the Affimetrix array; V. Petkova for assistance with Taqman; E. Rosen, Y.-B. Kim and Y. Minokoshi for helpful suggestions; and C. Wason for technical help. We thank J. E. Smith and B. Mickelson for advice regarding incorporation of fenretinide into rodent diets. Fenretinide was provided by the R. W. Johnson Pharmaceutical Company with the assistance of the National Cancer Institute's Cancer Therapy Evaluation Program. This work was supported by grants from the NIH (B.B.K and W. Blaner), Takeda Pharmaceutical Company Limited (B.B.K.) and the American Diabetes Association (B.B.K.). T.E.G. and J.M.Z. were supported by NIH career awards, F.P. by a Swiss National Science Foundation fellowship, and N.M. by an American Heart Association fellowship.

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Correspondence to Barbara B. Kahn.

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Competing interests

The project was partially supported by a research grant from Takeda Pharmaceutical Company Limited (Osaka, Japan).

Supplementary information

Supplementary Methods

Methods, including animal husbandry and diet; microarray analysis; measurement of metabolic parameters, insulin tolerance tests (ITT), glucose tolerance tests (GTT); and expression and purification of recombinant hRBP4. (DOC 27 kb)

Supplementary Tables S1-S2

Supplementary Table S1 shows the clinical parameters of human subjects. Supplementary Table S2 shows metabolic parameters of RBP4 transgenic and Rbp4 knockout mice. (DOC 72 kb)

Supplementary Figures S1-S2

Supplementary Figure S1 shows a correlation between serum RBP4 levels and insulin levels in obese mice on a high-fat diet. Supplementary Figure S2 shows western blot data comparing serum RBP4 levels in the mouse models that were studied. (PPT 34 kb)

Supplementary Figure Legends S1-S2 (DOC 25 kb)

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Yang, Q., Graham, T., Mody, N. et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 436, 356–362 (2005) doi:10.1038/nature03711

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