0111 Leptin Receptor Blockade Decreased Blood Pressure and Hypoxic Ventilatory Response in an Animal Model of Metabolic Syndrome

Abstract

Introduction: Human obesity leads to resistance to metabolic effects of leptin. Moreover, hyperleptinemia has been associated with hypertension and sleep disordered breathing. Leptin deficiency leads to hypoventilation in ob/ob mice, but effects of leptin receptor blockade on breathing are unknown. Here we utilized NZO mice, a model of metabolic syndrome with obesity-induced hypertension and hyperleptinemia, and hypothesize that a leptin receptor blocker will abolish hypertension and decrease hypoxic ventilatory response (HVR). Methods: Male NZO mice of 12-13 weeks-old housed in the 12:12-h light-dark cycle (lights on at 9AM) were treated with a leptin receptor antagonist Allo-aca for 9 consecutive days (0.2mg/ kg, 2x/day, at 10AM and 6PM, subcutaneously). Blood pressure was measured by telemetry. Ventilation was assessed by wholebody barometric plethysmography. For HVR, the animals were exposed to 30 minutes of normoxia followed by 5 minutes of hypoxia (10% O2 + 3% CO2) (3x/day). Sleep studies were conducted by full-polysomnography (10AM-4PM). Glucose levels were measured after 5h fasting. Results: Leptin receptor blocker induced a decrease in the mean arterial blood pressure during the light phase from 132.0±7.0 mmHg at baseline to 117.0±9.3 mmHg after treatment. Fasting glucose levels did not change after treatment. There was a significant decrease in the HVR from 2.3±0.1 mL/min/ΔSpO2 at baseline to 1.8±0.2 mL/min/ΔSpO2 after treatment. Allo-aca suppressed minute ventilation during NREM and REM sleep without a change in the oxygen desaturation index. Conclusion: A leptin receptor blocker Allo-aca abolished hypertension and decreased HVR in NZO mice with polygenic obesity and metabolic syndrome. However, mice developed hypoventilation, similar to that observed in leptin deficient ob/ob mice. Thus, leptin receptor blockers should be examined for treatment of hypertension in obese patients, but more selective approach sparing respiratory effects of leptin may be required.