Sedentary behavior is associated with an attenuated thermogenic response to beta-adrenergic receptor (beta-AR) stimulation, an important regulator of energy expenditure (EE) in humans. Chronic stimulation of beta-ARs, via heightened activity of the sympathoadrenal system, leads to diminished beta-AR function. We have investigated the hypothesis that the thermogenic response of sedentary adults to beta-AR stimulation will be increased during short-term sympathoadrenal inhibition. Using a randomly ordered, repeated measures study design, resting EE (REE; indirect calorimetry, ventilated hood technique) and the % increase in EE above REE (%DeltaEE) during acute i.v. isoproterenol administration (nonselective beta-AR agonist; 6, 12, and 24 ng/kg fat-free mass per min) were determined in 16 sedentary adults (nine females and seven males, 25+/-1 years, body mass index: 26.1+/-0.9 kg/m(2), maximal oxygen uptake: 40+/-2 ml/kg per min (mean+/-s.e.m.)) in the basal state and on the 6th day of transdermal clonidine administration (centrally acting alpha2-AR agonist; 0.2 mg/day). Relative to baseline, clonidine inhibited sympathoadrenal activity, as evidenced by decreased plasma norepinephrine concentration (1.04+/-0.13 vs 0.34+/-0.03 nmol/l; P<0.001), skeletal muscle sympathetic nerve activity (22.5+/-3.8 vs 8.5+/-1.9 bursts/min; P=0.003), and resting heart rate (63+/-2 vs 49+/-1 beats/min; P<0.001). Sympathoadrenal inhibition decreased REE (6510+/-243 vs 5857+/-218 kJ/day; P<0.001), increased respiratory exchange ratio (0.84+/-0.01 vs 0.86+/-0.01; P=0.03), and augmented the thermogenic response to beta-AR stimulation (%DeltaEE: 11+/-2, 16+/-2, and 24+/-2 vs 14+/-1, 20+/-2, and 31+/-2; P=0.04). These data demonstrate that in sedentary humans, short-term inhibition of sympathoadrenal activity increases the thermogenic response to beta-AR stimulation, an important determinant of EE and hence energy balance.