The effect of an infusion of norepinephrine (0.42 nmol.kg-1.min-1) on energy metabolism in the whole body (using indirect calorimetry and the arteriovenous forearm catheterization techniques in eight healthy young male adults. The activity of the triglyceride-fatty acid cycle, which mainly operates in nonmuscular tissues, was also assessed by measuring glycerol turnover using [2H5]glycerol (to indicate lipolysis) and indirect calorimetry (to indicate net fat oxidation). Norepinephrine increased whole body oxygen consumption by almost 10% (P < 0.01), but the estimated oxygen consumption of muscles tended to decrease. Muscle blood flow (measured by 133Xe) and forearm blood flow (measured by strain-gauge plethysmography) were not significantly affected by norepinephrine, but the rate of uptake of nonesterified fatty acids and beta-hydroxybutyrate increased severalfold (P < 0.05), whereas that of glucose did not. The activity of the triglyceride-fatty acid cycle increased fourfold after norepinephrine administration, having a marginal effect on resting energy expenditure (approximately 1.5%) but accounting for approximately 15% of the increase in whole body energy expenditure. This study provides no evidence that skeletal muscle is an important site for norepinephrine-induced thermogenesis and suggests that an increase in the activity of the triglyceride-fatty acid cycle contributes to the norepinephrine-induced increase in energy expenditure of nonmuscular tissues.