Hexosamines regulate leptin production in human subcutaneous adipocytes

The hexosamine biosynthetic pathway has recently been proposed as a mechani sm through which cells "sense" nutrient flux to regulate leptin release. Th is study was undertaken to examine the regulation of leptin production by h exosamines in human adipocytes. Adipose tissue UDP-N-acetylglucosamine, an end product of hexosamine biosynthesis, was elevated 3.2-fold, and ob messe nger ribonucleic acid was elevated a-fold in the sc adipose tissue of 17 ob ese [body mass index (BMI), 41.3 +/- 12.0 kg/m(2); age, 31 +/- 5 yr] subjec ts compared to 14 lean (BMI, 23.4 +/- 1.6 kg/m(2); age, 33 +/- 11yr) subjec ts. Serum leptin was increased 2.7-fold in the obese subjects. A significan t positive relationship was found between adipose tissue UDP-N-acetylglucos amine and BMI (Spearman correlation = 0.576; P = 0.0007) and between UDP-N- acetylglucosamine and serum leptin (Spearman correlation = 0.4650; P = 0.01 45). Treatment of isolated sc adipocytes with 1 mmol/L glucosamine, an inte rmediate 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, re spectively, by 48 h of culture. Inhibition of UDP-N-acetylglucosamine biosy nthesis with 6-diazo-5-oxo-norleucine reduced glucose-stimulated leptin rel ease from cultured adipocytes 21.8 +/- 32.4% (P = 0.0395; n = 12) and ob ge ne expression 19.9 +/- 18.9% (P = 0.0208; n = 8) by 48 b of treatment. Thes e findings suggest that hexosamine biosynthesis regulates leptin production in human adipose tissue.