Leptin, which plays a key role in regulating energy homeostasis, may also modulate the inflammatory response. An inflammatory challenge with endotoxin has been shown to stimulate leptin release in the rodent. This finding has not been reproduced in humans or in nonhuman primates, although leptin levels have been reported to increase in septic patients. We have therefore examined the effects of endotoxin injection on plasma leptin levels in nine ovariectomized monkeys and four postmenopausal women. In an initial study in five monkeys, mean leptin levels did not increase during the first 5 h after endotoxin treatment, but did increase significantly from 6.4 +/- 2.1 ng/ml at baseline to 12.3 +/- 4.4 ng/ml at 24 h (P = 0.043). In a second study, a significant increase in leptin over time was noted after endotoxin treatment (P < 0.001); leptin release during the 16- to 24-h period after endotoxin injection was 48% higher than during the control period (P = 0.043). A similar stimulatory effect of endotoxin on leptin was observed when monkeys received estradiol replacement. In a third study, repeated injections of endotoxin over a 3-d period stimulated IL-6, ACTH, cortisol, and leptin release (P < 0.001). Leptin increased during the first day of treatment in all animals, but only monkeys with baseline plasma leptin levels greater than 10 ng/ml exhibited a sustained increase in leptin throughout the 3-d period. There was a significant correlation (r = 0.81; P = 0.008) between the mean baseline leptin level and the percent increase in leptin over baseline on the last day of treatment. In the human subjects, plasma leptin concentrations did not change significantly during the 7-h period after endotoxin injection. However, leptin increased in all four women from a mean baseline of 8.34 +/- 3.1 to 13.1 +/- 4.3 ng/ml 24 h after endotoxin (P = 0.038). In summary, endotoxin stimulates the release of leptin into peripheral blood in the human and nonhuman primate, but the time course is different from that reported in the rodent. These results are consistent with previous reports of increased blood leptin levels in patients with sepsis. The significance of these findings and the potential role of leptin in modulating the response to inflammation in the human require further study.