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

doi:10.1038/nature03711

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

School of Environmental and Biological Sciences, Food Science

Research output: Contribution to journal › Article › peer-review

1679 Scopus citations

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-Gluf4^-/- 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 language	English (US)
Pages (from-to)	356-362
Number of pages	7
Journal	Nature
Volume	436
Issue number	7049
DOIs	https://doi.org/10.1038/nature03711
State	Published - Jul 21 2005

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@article{a9aa6ce9bc714193a755b446d3d0ba10,

title = "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-Gluf4-/- 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.",

author = "Qin Yang and Graham, {Timothy E.} and Nimesh Mody and Frederic Preitner and Peroni, {Odile D.} and Zabolotny, {Janice M.} and Ko Kotani and Loredana Quadro and Kahn, {Barbara B.}",

note = "Funding Information: 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{\textquoteright}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.",

year = "2005",

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day = "21",

doi = "10.1038/nature03711",

language = "English (US)",

volume = "436",

pages = "356--362",

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T1 - Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes

AU - Yang, Qin

AU - Graham, Timothy E.

AU - Mody, Nimesh

AU - Preitner, Frederic

AU - Peroni, Odile D.

AU - Zabolotny, Janice M.

AU - Kotani, Ko

AU - Quadro, Loredana

AU - Kahn, Barbara B.

N1 - Funding Information: 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.

PY - 2005/7/21

Y1 - 2005/7/21

N2 - 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-Gluf4-/- 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.

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-Gluf4-/- 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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Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes

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