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Retinol Binding Protein 4 Expression in Humans: Relationship to Insulin Resistance, Inflammation, and Response to Pioglitazone

The Central Arkansas Veterans Healthcare System, and the Department of Medicine, Division of Endocrinology (A.Y.-B., V.V., A.M.B., N.R., B.P., T.S., L.M.K., A.A.R., P.A.K.), and Departments of Biostatistics (H.J.S.) and Pediatrics (R.E.M.), University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205; and Department of Medicine (M.-J.L., S.K.F.), University of Maryland, Baltimore, Maryland 21201

Address all correspondence and requests for reprints to: Philip A. Kern, M.D., Research, 598/151, Central Arkansas Veterans Healthcare System, 4300 West 7th Street, Little Rock, Arkansas 72205. E-mail: KernPhilipA{at}uams.edu.

Context: Retinol binding protein 4 (RBP4) was recently found to be expressed and secreted by adipose tissue, and was strongly associated with insulin resistance.

Objective: The aim was to determine the relationship between RBP4 and obesity, insulin resistance, and other markers of insulin resistance in humans.

Design and Patients: RBP4 mRNA levels in adipose tissue and muscle of nondiabetic human subjects with either normal or impaired glucose tolerance (IGT) were studied, along with plasma RBP4. RBP4 gene expression was also measured in adipose tissue fractions, and from visceral and sc adipose tissue (SAT) from surgical patients.

Setting: The study was conducted at University Hospital and General Clinical Research Center.

Intervention: Insulin sensitivity (S_I) was measured, and fat and muscle biopsies were performed. In IGT subjects, these procedures were performed before and after treatment with metformin or pioglitazone.

Main Outcome Measures: The relationship between RBP4 expression and obesity, S_I, adipose tissue inflammation, and intramyocellular lipid level, and response to insulin sensitizers was measured.

Results: RBP4 was expressed predominantly from the adipocyte fraction of SAT. Although SAT RBP4 expression and the plasma RBP4 level demonstrated no significant relationship with body mass index or S_I, there was a strong positive correlation between RBP4 mRNA and adipose inflammation (monocyte chemoattractant protein-1 and CD68), and glucose transporter 4 mRNA. Treatment of IGT subjects with pioglitazone resulted in an increase in S_I and an increase in RBP4 gene expression in both adipose tissue and muscle, but not in plasma RBP4 level, and the in vitro treatment of cultured adipocytes with pioglitazone yielded a similar increase in RBP4 mRNA.

Conclusions: RBP4 gene expression in humans is associated with inflammatory markers, but not with insulin resistance. The increase in RBP4 mRNA after pioglitazone treatment is unusual, suggesting a complex regulation of this novel adipokine.

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