Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes
Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes
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DOI：
10.1038/nature03711
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发表时间：
2005-07-21
期刊：
影响因子：
64.8
通讯作者：
Kahn, BB
中科院分区：
文献类型：
--
作者：
Yang, Q;Graham, TE;Kahn, BB
在肥胖症和2型糖尿病中，脂肪细胞中GLUT 4葡萄糖转运蛋白的表达选择性降低。脂肪特异性Glut4（也称为Slc2a4）敲除（adipose-Glut4（-/-））小鼠在肌肉和肝脏中显示继发性胰岛素抵抗。在这里，我们显示，使用DNA阵列，视黄醇结合蛋白-4（RBP4）的表达在脂肪-谷氨酸4（-/-）小鼠的脂肪组织中升高。我们发现，血清RBP4水平在胰岛素抵抗小鼠和肥胖和2型糖尿病患者中升高。胰岛素增敏药物罗格列酮使RBP4水平正常化。转基因过表达人RBP4或注射重组RBP4在正常小鼠中引起胰岛素抵抗。相反，Rbp4的基因缺失增强胰岛素敏感性。芬维A胺是一种合成类维生素A，可增加尿中RBP4的排泄，使血清RBP4水平正常化，并改善高脂饮食诱导的肥胖小鼠的胰岛素抵抗和葡萄糖耐受不良。增加血清RBP4诱导肝脏表达的致炎酶磷酸烯醇式丙酮酸羧激酶（PEPCK），并损害肌肉中的胰岛素信号传导。因此，RBP4是脂肪细胞来源的“信号”，可能有助于2型糖尿病的发病机制。降低RBP4可能是治疗2型糖尿病的新策略。
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.