This study examined the importance of direct CNS actions and increased adrenergic activity in mediating the chronic antidiabetic and cardiovascular actions of leptin. Insulin-deficient rats (streptozotocin, 50 mg/kg) were used to examine the effects of leptin on glucose homeostasis independent of changes in insulin. Male Sprague-Dawley rats were instrumented with arterial and venous catheters and intracerebroventricular (ICV) for 24-h/d blood pressure (BP) and heart rate (HR) monitoring and IV and ICV infusions. Insulin-deficient diabetes was associated with marked hyperglycemia, hyperphagia, decreased BP, and pronounced fall in HR. Leptin treatment, IV or ICV, completely restored to control values plasma glucose levels (384 ± 58 to 102 ± 28 and 307 ± 38 to 65 ± 7 mg/dl, respectively), food intake, BP and HR (304 ± 8 to 364 ± 7 and 317 ± 13 to 423 ± 9 bpm, respectively). Combined 1, 1 and 2 adrenergic receptors blockade attenuated the rise in HR by 30 to 50%, but had no effect on the antidiabetic and dietary actions of leptin. Blockade of 3 adrenergic receptors did not attenuate the chronic cardiovascular or metabolic effects of leptin. These data demonstrate that leptin, via its direct actions in the CNS, has powerful antidiabetic actions in insulin-deficient rats independent of increased peripheral 1, 1, 2, and 3 adrenergic activity. Leptin also exerts important long-term cardiovascular actions that are partially mediated via 1 and 1/2 adrenergic activation. These findings provide new insights into novel pathways for long-term control of glucose homeostasis and cardiovascular regulation.