Vascular control of nonshivering thermogenesis in the perfused hind limb of obese and lean Zucker rats were compared using two vasoconstrictors, norepinephrine and serotonin. For hind limbs of both phenotypes, norepinephrine infusions resulted in a dose-dependent uninterrupted increase in perfusion pressure and a biphasic change in oxygen uptake (VO2), characterized by a stimulation at low concentrations, and an increasing inhibition at higher concentrations that gradually overcame the stimulation in a dose-dependent manner. At concentrations of norepinephrine greater than 1 microM, the inhibitory effect predominated and gave rise to values for VO2 less than basal. The obese hind limb had a lower basal VO2 and a lower maximal VO2 mediated by norepinephrine than the lean rat, but these differences appeared to relate largely to the lower muscle mass and higher content of fat of the obese hind limb. Serotonin infusions resulted in dose-dependent increase in perfusion pressure and an accompanying decrease in VO2. Pressure changes were identical for the obese and lean hind limbs, but the decrease in VO2 due to serotonin was greater in the hind limbs from the lean rats, and this difference remained when the data were expressed in terms of muscle mass perfused. It is concluded that the relatively lower content of muscle of the obese hind limb accounts for its lower basal and lower maximal norepinephrine-mediated thermogenesis. In addition, an intrinsic defect in obese hind limb muscle response to serotonin is present, which may be indicative of a decrease in the potential for vasoconstrictor-regulated thermogenesis that could have implications for whole-body energy balance by the obese phenotype.