beta-Adrenergically mediated thermogenic and heart rate (HR) responses, as assessed by stepwise intravenous infusion of the beta-agonist isoprenaline (ISO), were evaluated by partial regression analysis in a group of men with a wide range of body fat (n = 30) and in a subgroup of 16 obese men after weight loss. beta-Adrenergically mediated thermogenesis (open-circuit ventilated-hood system) was blunted in obese subjects, as reflected by a significant positive correlation between percent body fat (hydrostatic weighing) and the plasma ISO concentration needed to increase resting energy expenditure (EE) by 15% (P < .001). The magnitude of the beta-adrenergically mediated HR response was (negatively) associated with the basal plasma norepinephrine (NE) concentration (P < .001). Weight reduction resulted in a significant increase in thermogenic and HR responses in obese subjects. Furthermore, the increase in thermogenic response as a result of weight loss was negatively related to the magnitude of thermogenic response (P < .01) and positively related to the initial percent body fat (P < .05). The increase in HR response as a result of weight loss was positively related to the decrease in basal NE (P < .01) and the change in percent body fat (P < .05). In conclusion, the degree of adiposity was shown to be negatively related to the magnitude of beta-adrenergically mediated thermogenesis, whereas the HR response was merely related to basal NE. Since weight loss resulted in a significant increase in the thermogenic response, the blunted beta-adrenergically mediated thermogenesis does not seem to be a primary factor contributing to the development of obesity.