Abstract 13439: Leptin Inhibits Heart Rate Via its Receptor
It has been widely accepted that leptin increases heart rate via beta-adrenergic stimulation in obese humans. This conclusion, however, fails to explain the clinical observation that up to 19% of obese individuals have sinus bradycardia. The presence of adipocytes in human myocardium raised a question as to whether leptin can directly modulate heart rate via its own receptor.
To answer this question, we firstly performed electrocardiography in intact rat in vivo and found that within 5-10min leptin decreased the resting heart rate by 4.3% at a concentration of 1μg/kg and 9.1% at 100μg/kg. A high-dose of leptin (300μg/kg) exerted biphasic effects, a reduction (for 3 minutes) followed by an increase of heart rate for 2 minutes and reached a steady state that is higher than the basal heart rate. In the presence of propranolol (30mg/kg), leptin (150μg/kg) can still reduce the heart rate. In dissected sinus node, leptin at a comparable concentration consistently decreased the pacing rate and inhibited the positive chronotropic effects of isoproterenol. Distinct from enhancing heart rate in vivo, increased concentrations of leptin even induced a sinus pause ex vivo. Utilizing an obese rat model (obese Zucker rat), we noticed that adipocytes are significantly accumulated in right cardiac atrium that lies in close proximity to the sinus node, which was not observed in the lean controls. Further, confocal fluorescence microscopy revealed that ObRb, the signaling-form of leptin receptor, was selectively expressed at the cell surface of sinus node myocytes. Finally, whole-cell electrophysiology was conducted to investigate the effects of leptin on the cardiac pacemaker channel (HCN4) in vitro. Leptin inhibited HCN4 currents only when ObRb was coexpressed in human embryonic kidney (HEK) 293 cells. Consistent to the reduction in current amplitude after leptin treatment, the surface expression of HCN4 was also reduced in the presence of leptin.
In conclusion, our results demonstrated that leptin directly inhibits sinus pacing via its receptor and HCN4 channel acts as one of its downstream effectors, suggesting a novel role of cardiac leptin receptor signaling toward modulation of heart rate independent of beta-adrenergic receptor.
- © 2013 by American Heart Association, Inc.