Hexosamines regulate leptin production in human subcutaneous adipocytes

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 a-fold in the sc adipose tissue of 17 obese [body mass index (BMI), 41.3 +/- 12.0 kg/m(2); age, 31 +/- 5 yr] subjects compared to 14 lean (BMI, 23.4 +/- 1.6 kg/m(2); age, 33 +/- 11yr) 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/m(2); 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 b of treatment. These findings suggest that hexosamine biosynthesis regulates leptin production in human adipose tissue.