Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes.
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.
Yang
Qin
Q
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Graham
Timothy E
TE
Mody
Nimesh
N
Preitner
Frederic
F
Peroni
Odile D
OD
Zabolotny
Janice M
JM
Kotani
Ko
K
Quadro
Loredana
L
Kahn
Barbara B
BB
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D051275:Glucose Transporter Type 4; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D009004:Monosaccharide Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000097:blood* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D012177:Retinol-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D054839:Retinol-Binding Proteins, Plasma; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology
D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C502487:Rbp4 protein, mouse; D012177:Retinol-Binding Proteins; D054839:Retinol-Binding Proteins, Plasma; C495693:Slc2a4 protein, mouse; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D010729:Phosphoenolpyruvate Carboxykinase (GTP)