Our previous work showed that ob/ob mice responded to physiological concentrations of blood corticosterone (maintained by implanted pellets of corticosterone in adrenalectomized mice) by increasing food intake and blood insulin concentration to a much greater extent than did lean mice. The present study sought to determine whether the chronic presence of corticosterone was necessary or whether a single injection would also have these effects. Lean and ob/ob mice were adrenalectomized at 4.5 wk of age, injected with corticosterone at 10.5 wk of age, and killed 6 or 15 h after injection. A markedly exaggerated hyperinsulinemia was seen in ob/ob mice at 15 h. Food intake increased in both lean and obese mice, and brown adipose tissue thermogenesis (as reflected by mitochondrial guanosine 5'-diphosphate binding) was suppressed in both. We conclude that the ob/ob mouse has an excessive central sensitivity and responsiveness to a rapid action of corticosterone that results in neural activation of insulin secretion and suppression of brown adipose tissue thermogenesis. The persistence of some degree of obesity in the adrenalectomized ob/ob mouse is attributed to the remaining slight hyperinsulinemia coupled with reduced energy expenditure due to persistent thermoregulation at a lower than normal body temperature.