Chronic antidiabetic and cardiovascular actions of leptin: role of CNS and increased adrenergic activity

This study examined the importance of direct central nervous system (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 cannula for 24-h/day blood pressure (BP) and heart rate (HR) monitoring and intravenous and intracerebroventricular infusions. Insulin-deficient diabetes was associated with marked hyperglycemia, hyperphagia, decreased BP, and pronounced fall in HR. Leptin treatment, intravenous or intracerebroventricular, 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 blockade of alpha(1)-, beta(1)-, and beta(2)-adrenergic receptors attenuated the rise in HR by 30 to 50% but had no effect on the antidiabetic and dietary actions of leptin. Blockade of beta(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 alpha(1), beta(1), beta(2), and beta(3)-adrenergic activity. Leptin also exerts important long-term cardiovascular actions that are partially mediated via alpha(1)- and beta(1)/beta(2)-adrenergic activation. These findings provide new insights into novel pathways for long-term control of glucose homeostasis and cardiovascular regulation.