We have studied the effect of fasting on serum leptin levels in normal volunteers. Five normal-weight (BMI < 28, 2 males/3 females) and five obese subjects (BMI > 28, 2 males/3 females) were fasted (0 Kcal) for 52 h. Mean plasma glucose decreased from 88 +/- 3 to 63 +/- 5 mg/dl, serum insulin from 16 +/- 1 to 10 +/- 1 microU/ml, plasma beta-hydroxybutyrate increased from 0.2 +/- 0.1 to 1.8 +/- 0.4 mumol/ml. Serum leptin levels were higher in the obese than in the normal-weight volunteers (31 +/- 12 vs 11 +/- 3 ng/ml, p < 0.01). In the obese, serum leptin decreased from 31 +/- 10 to 12 +/- 5 ng/ml aft552 h (-72%, p < 0.001); in the normal-weight it decreased from 11 +/- 3 to 4 +/- 0.5 ng/ml (-64%, p < 0.001). Serum leptin correlated positively with serum insulin (r = 0.51, p < 0.001) and with plasma glucose (r = 0.61, p < 0.001). To determine effects of fasting induced decreases in plasma glucose and insulin on serum leptin, four normal subjects (3 males/1 female) were fasted for 72 h while their plasma glucose was clamped at basal levels with a variable rate glucose infusion. In these volunteers, serum leptin and insulin concentrations remained unchanged. In summary, the rapid decrease in serum leptin levels during fasting indicated that leptin release was regulated by factors other than changes in body fat mass. The lack of leptin changes during fasting, when basal insulin and glucose levels were maintained at basal levels, suggested that insulin and/or glucose may play a role in the regulation of leptin release.