The effect of beta-adrenergic stimulation on whole body energy expenditure and forearm skeletal muscle metabolism was investigated in lean and obese men. Whole body energy expenditure was determined during rest and during intravenous infusion of increasing doses of the nonselective beta-agonist isoprenaline (Iso). Forearm skeletal muscle metabolism was investigated with Iso infusion with and without simultaneous infusion of the beta 1-blocker atenolol (AT) by measuring skeletal muscle blood flow (SMBF) and arteriovenous concentration differences of various metabolites. The changes in SMBF were estimated from forearm total (venous occlusion plethysmography), skin (laser doppler), and fat tissue blood flow (133Xe washout). The increase in whole body energy expenditure with Iso was similar in lean and obese subjects. With Iso, the rise in arterial or arterialized glycerol and nonesterified fatty acids (NEFA) was lower in obese than lean subjects, which may reflect a lower beta-adrenergically mediated lipolysis in obesity. During infusion of increasing doses of Iso, the respiratory exchange ratio decreased significantly in lean subjects but not in the obese subjects, which indicates a more pronounced increase in fat oxidation in lean subjects. This is confirmed by the data on skeletal muscle metabolism, where NEFA uptake was increased in lean subjects, whereas the obese subjects showed a tendency toward an increased glucose uptake and a significantly increased lactate release. With Iso plus AT (mainly beta 2-adrenergic stimulation), both groups showed an increased skeletal muscle lactate release. In conclusion, although the thermogenic response to Iso was similar in lean and obese subjects, the utilization of fat seems to be impaired in obesity.