We studied the interrelationship between the obese gene product serum leptin, insulin and counter-regulatory hormone concentrations and glycogen synthesis in 26 healthy men. A 4-h euglycaemic insulin clamp with muscle biopsies was performed after a resting control day in 26 subjects, and in 14 of them also after heavy, glycogen-depleting (32%, P < 0.01) exercise. Serum leptin concentrations were at baseline 34% (0.67 +/- 0.18 vs. 1.03 +/- 0.13 ng L-1, P < 0.05) lower after the exercise, and rose during hyperinsulinaemia by 56% (to 1.38 +/- 0.19 ng L-1, P < 0.001) and 34% (to 1.05 +/- 0.20 ng L-1, P < 0.01) after the post-exercise and control studies respectively. Basal serum leptin concentration correlated positively with body mass index (r = 0.42, P < 0.05), serum cortisol concentration (r = 0.70, P < 0.001) and the rise in muscle glycogen content during the clamp (r = 0.43, P < 0.05) and inversely with serum growth hormone concentration (r = -0.43, P < 0.05). There was a positive correlation between serum leptin after hyperinsulinaemia and serum insulin concentration during the hyperinsulinaemia (r = 0.42, P < 0.05). After exercise, basal serum leptin level correlated with serum triglyceride concentration (r = 0.82, P < 0.001) and after hyperinsulinaemi serum leptin correlated positively with muscle glycogen content (r = 0.56, P < 0.05). It was concluded that serum leptin concentrations correlate directly with serum insulin, cortisol and triglyceride and inversely with growth hormone concentrations. They are decreased by glycogen-depleting exercise and increase during hyperinsulinaemic clamp. These data suggest that leptin is associated with factors regulating fuel homeostasis and its hormonal control in man.