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

Q Yang, TE Graham, N Mody, F Preitner, OD Peroni… - Nature, 2005 - nature.com
Q Yang, TE Graham, N Mody, F Preitner, OD Peroni, JM Zabolotny, K Kotani, L Quadro
Nature, 2005nature.com
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 …
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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