The physiological significance of changes in uncoupling protein-2 (UCP-2) gene expression is controversial. In this study we investigated the biochemical and functional correlates of UCP-2 gene expression in sc abdominal adipose tissue in humans in vivo. UCP-2 messenger ribonucleic acid expression was quantified by nuclease protection in adipose tissue from lean and obese humans in both the fasting and postprandial states. Plasma fatty acids, insulin, and leptin were all determined in paired samples from the superficial epigastric vein and radial artery, and local production rates were calculated from 133Xe washout. In the fasting state UCP-2 expression correlated inversely with body mass index (r = -0.45; P = 0.026), percent body fat (r = -0.41; P = 0.05), plasma insulin (r = -0.47; P = 0.02), epigastric venous fatty acids (r = -0.45; P = 0.04), and leptin (r = -0.50; P = 0.018). UCP-2 expression remained inversely related with plasma leptin after controlling for percent body (r = -0.45; P = 0.038). At 2 or 4 h postprandially, there were no significant relationships between UCP-2 expression and biochemical parameters. In conclusion, 1) UCP-2 messenger ribonucleic acid expression in sc adipose tissue is inversely related to adiposity and independently linked to local plasma leptin levels; and 2) UCP-2 expression is not acutely regulated by food intake, insulin, or fatty acids. Reduced UCP-2 expression may be a maladaptive response to sustained energy surplus and could contribute to the pathogenesis and maintenance of obesity.