The recently discovered leptin is thought to be a satiety signal regulating food intake. In mice, it has been shown that on a high-fat diet leptin concentration increases, but the increase was explained by increased fat mass. It is yet unknown whether leptin is influenced by other nutritional factors. Here, leptin levels were measured in human volunteers on a high-fat diet, while maintaining energy balance. Twelve healthy, non-obese males and females (age, 26 +/- 2 years; 21.4 +/- 0.5 body mass index, habitual fat intake, 29 +/- 1 energy % [en%]) consumed a high-fat diet (60 en% fat) for 7 days (days 1 to 7). Subjects were in energy balance (range, -0.15 to +0.23 MJ/d) as measured in a respiration chamber on days 1 to 3 and 7. Fasting baseline plasma leptin concentrations correlated with body fat percentage (R2 = .64, P < .005). On average, no changes in leptin concentration on the high-fat diet were observed. However, on an individual basis, changes in leptin concentrations in response to the high-fat diet correlated with changes in insulin concentrations. In conclusion, in the case of energy balance, short-term changes in diet composition have no effect on fasting leptin concentration in lean subjects.