Leptin, an adipose tissue-derived cytokine, is correlated with adipose mass as obese persons have increased levels of leptin that decrease with weight-loss. Previous studies demonstrate that high-energy expenditure exercise decreases circulating leptin levels, whereas low-energy expenditure exercise has no effect. We aimed to test the hypothesis that acute exercise reduced leptin mRNA levels in human adipose tissue, and that this effect would be ameliorated by carbohydrate supplementation. As exercise markedly increases circulating IL-6 and epinephrine, we investigated whether the changes in leptin seen with acute exercise could be mediated by IL-6 or epinephrine infusion. Abdominal subcutaneous adipose tissue mRNA and plasma levels of leptin were measured in healthy men in response to 3-hour ergometer exercise with or without CHO ingestion (n=8) and in response to infusion with recombinant human (rh)IL-6 (n=11) or epinephrine (n=8) or saline. Plasma leptin declined in response to exercise (P<0.05) when compared with rest whereas mRNA expression in adipose tissue was unaffected. The exercise-induced decrease in plasma leptin was attenuated by CHO ingestion (P<0.001). A 3-h epinephrine infusion decreased plasma leptin (p<0.001) to the same level seen with 3-h of exercise, whereas leptin levels were unaffected by rhIL-6 infusion. In conclusion, both acute exercise and epinephrine infusion decreased plasma leptin to a similar extent, whereas there was no effect with rhIL-6 infusion. Acute exercise solely affected leptin plasma levels, as mRNA levels were unchanged. The exerciseinduced decrease in circulating leptin was counteracted by CHO ingestion suggesting a post-transcriptional regulatory mechanism of leptin involving substrate availability.