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Hexosamines Regulate Leptin Production in Human Subcutaneous Adipocytes¹

Divisions of Endocrinology and Metabolism (R.V.C., L.B.W., R.L.F., P.Z.) and Biostatistics (W.T.A.), Department of Medicine, and Department of Surgery (R.M.W., R.M.J.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Surgery, St. Vincent’s Hospital (R.M.J., M.I., J.H.), Carmel, Indiana 46032; and Division of Endocrinology and Metabolism, Department of Medicine, University of Utah School of Medicine (R.C.C., D.A.M.), and Veterans Affairs Medical Center, Salt Lake City, Utah 84132

Address all correspondence and requests for reprints to: Robert V. Considine, Ph.D., Indiana University School of Medicine, 541 North Clinical Drive, Clinical Building 455, Indianapolis, Indiana 46202-5111. E-mail: rconsidi{at}iupui.edu

The hexosamine biosynthetic pathway has recently been proposed as a mechanism through which cells "sense" nutrient flux to regulate leptin release. This study was undertaken to examine the regulation of leptin production by hexosamines in human adipocytes. Adipose tissue UDP-N-acetylglucosamine, an end product of hexosamine biosynthesis, was elevated 3.2-fold, and ob messenger ribonucleic acid was elevated 2-fold in the sc adipose tissue of 17 obese [body mass index (BMI), 41.3 ± 12.0 kg/m²; age, 31 ± 5 yr] subjects compared to 14 lean (BMI, 23.4 ± 1.6 kg/m²; age, 33 ± 11 yr) subjects. Serum leptin was increased 2.7-fold in the obese subjects. A significant positive relationship was found between adipose tissue UDP-N-acetylglucosamine and BMI (Spearman correlation = 0.576; P = 0.0007) and between UDP-N-acetylglucosamine and serum leptin (Spearman correlation = 0.4650; P = 0.0145). Treatment of isolated sc adipocytes with 1 mmol/L glucosamine, an intermediate product in UDP-N-acetylglucosamine biosynthesis, increased leptin release 21.4 ± 17.6% (mean ± SD) over control (P = 0.0365) and 74.5 ± 82.8% over control (P = 0.0271) in adipocytes from lean (BMI, 23.2 ± 1.6 kg/m²; n = 6) and obese (BMI, 55.4 ± 13.0 kg/m^2,; n = 9) subjects, respectively, by 48 h of culture. Inhibition of UDP-N-acetylglucosamine biosynthesis with 6-diazo-5-oxo-norleucine reduced glucose-stimulated leptin release from cultured adipocytes 21.8 ± 32.4% (P = 0.0395; n = 12) and ob gene expression 19.9 ± 18.9% (P = 0.0208; n = 8) by 48 h of treatment. These findings suggest that hexosamine biosynthesis regulates leptin production in human adipose tissue.

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