Leptin is considered an adipokine, however, cultured myocytes have also been found to release leptin. Therefore, as proof-of-concept we investigated if human skeletal muscle synthesized leptin by measuring leptin in skeletal muscle biopsies. Following this, we quantified human skeletal muscle and adipose tissue leptin release in vivo. We recruited 16 healthy male human participants. Catheters were inserted into the femoral artery and vein draining skeletal muscle, as well as an epigastric vein draining the abdominal subcutaneous adipose tissue. By combining the veno-arterial differences in plasma leptin with measurements of blood flow, leptin release from both tissues was quantified. To induce changes in leptin, the participants were infused with either saline or adrenaline in normo-physiological concentrations. The presence of leptin in skeletal muscle was confirmed by western blotting. Leptin was released from leg skeletal muscle (50.6 ± 12 ng min(-1)) and the pattern of release was different from subcutaneous adipose tissue. Moreover, during adrenaline infusion the leptin release from leg skeletal muscle was strongly suppressed (20.5 ± 7.9 ng min(-1), p<0.017), whereas the release from fat was unaltered. During saline infusion the adipose tissue release averaged 0.8 ± 0.3 ng min(-1) 100g tissue(-1) whereas skeletal muscle release was 0.5 ± 0.1 ng min(-1) 100g tissue(-1). In young healthy humans, skeletal muscle contribution to whole body leptin production could be substantial given the greater mass of muscle compared to fat. An understanding of the role that leptin plays in skeletal muscle metabolism may prove important in light of several late-phase trials with recombinant leptin as an anti-obesity drug