Central Leptin Infusion Attenuates the Cardiovascular and Metabolic Responses to Negative Energy Balance

Abstract

65 Caloric restriction is commonly prescribed to obese individuals to reduce their risk for cardiovascular disease. Hypothalamic pathways regulated by leptin are important in activating homeostatic responses to reduced caloric intake. We tested the hypothesis that central infusion of leptin would prevent reductions in blood pressure (BP), heart rate (HR), and oxygen consumption (VO 2 ) produced by acute caloric deprivation. Male Sprague-Dawley rats were instrumented with telemetry devices for measuring blood pressure and icv guide cannulae for chronic infusion of vehicle or murine leptin. After 10 d of recovery, rats were housed in metabolic chambers for continuous assessment of BP and HR by telemetry, and VO 2 and respiratory quotient (RQ) by indirect calorimetry. For group comparisons, data were averaged for the light (inactive) and dark (active) phases. After obtaining baseline data (3 days), rats (n=22) were briefly anesthetized with halothane to attach osmotic pumps containing either vehicle (PBS, 0.5 μl/h) or leptin (42 ng/h) for chronic icv infusion during either ad lib feeding or 48h of fasting. In ad lib feeding animals (n=5) receiving PBS infusions, transient (24 h) reductions in caloric intake and active phase VO 2, with no effect on body weight, HR and MAP were observed. We attribute these effects to anesthesia required for pump attachment. After 48 h, leptin infusion (in ad lib animals; n=5) significantly reduced caloric intake (50-60%), body weight (-15±5 g) and RQ (-0.07±0.02); indicating lipolysis), while increasing HR (+28±4 bpm) and having no effect on MAP. Fasting reduced active phase MAP (-9±3 mmHg), HR (-60±3 bpm), and VO 2 (-25 %) in rats receiving PBS infusions (n=6). ICV leptin infusion (n=6) had no effect on the reduction in active phase MAP, but significantly attenuated fasting-induced active phase decreases in HR (-25±4 bpm) and VO 2 (-17%). In addition, leptin completely prevented fasting-induced decreases in inactive phase HR and VO 2 . The results are consistent with the hypothesis that reductions in central leptin signaling mediate the homeostatic decreases in HR and metabolic rate in response to acute caloric deprivation.