Leptin has been shown to diminish hyperglycemia via reduced glucagon secretion, although it can also enhance sympathoadrenal responses. Whether leptin can also inhibit glucagon secretion during insulin-induced hypoglycemia or increase epinephrine during acute or recurrent hypoglycemia has not, however, been examined. To test if leptin acts in the brain to influence counterregulation, hyperinsulinemic/hypoglycemic (~45 mg/dl) clamps were performed on rats exposed to or not exposed to recurrent hypoglycemia (3 days, ~40 mg/dl). Intracerebroventricular artificial cerebral spinal fluid or leptin were infused during the clamp. During acute hypoglycemia, leptin decreased glucagon responses by 51%, but increased epinephrine and norepinephrine by 24% and 48%, respectively. After recurrent hypoglycemia, basal plasma leptin levels were undetectable. Subsequent brain leptin infusion during hypoglycemia paradoxically increased glucagon by 45% as well as epinephrine by 19%. In conclusion, leptin acts within the brain to diminish glucagon secretion during acute hypoglycemia, but increases epinephrine potentially limiting its detrimental effects during hypoglycemia. Exposure to recurrent hypoglycemia markedly suppresses plasma leptin, whereas exogenous brain leptin delivery enhances both glucagon and epinephrine release to subsequent hypoglycemia. These data suggest that recurrent hypoglycemia may diminish counterregulatory responses in part by reducing brain leptin action.