Abstract 4876: Leptin Reverses Hyperlipidemia and Vascular Dysfunction in Mice Exposed to Intermittent Hypoxia

Abstract

Obesity and sleep apnea contribute to poor vascular health. Lack of leptin and exposure to intermittent hypoxia (IH) both lead to greater vascular stiffness and endothelial dysfunction, accompanied by dyslipidemia. We previously showed that leptin deficient ob/ob mice exposed to IH showed greater vascular stiffness, fully reversed with leptin repletion. In this study, we tested the hypothesis that leptin treatment in lean mice exposed to IH can improve dyslipidemia, vascular compliance and endothelial function. C57BL6/J mice with or without leptin infusion (0.3 mg/kg/day via subcutaneous osmotic pumps) were exposed to IH or room air for 4 weeks. Pulse wave velocity (PWV) was measured by Doppler to assess vascular stiffness (n=8–20). Vascular relaxation response to acetylcholine (ACh) was measured in preconstricted aortic rings (n=10–21) to indicate endothelial function. In mice exposed to room air, leptin did not affect PWV (3.53±0.07 vs. 3.48±0.04 m/s in control, p=NS) or endothelium-dependent relaxation (Emax 79.7±2.1 vs. 77.5±3.4 % in control; p=NS). Mice exposed to IH had higher PWV, i.e. increased vascular stiffness, vs. control (3.92±0.06 m/s; p<0.001). There was a trend toward improved PWV in IH+leptin mice (3.74±0.08 m/s; p=0.08 vs. IH, p<0.05 vs. control). ACh-induced aortic ring relaxation was attenuated in IH (Emax 65.5±2.0 %; p<0.001 vs. control) but normal in IH+leptin (Emax 78.1±1.8 %; p<0.001 vs. IH, p=NS vs. control). Fasting serum total cholesterol was lower in IH+leptin vs. IH mice (82.6±3.2 vs. 102.6±5.1 mg/dL, p<0.001), as was total triglycerides (26.3±3.5 vs. 38.3±3.4 mg/dL, p<0.05). Hepatic protein expression of stearoyl-Coenzyme A desaturase 1 (SCD-1), which catalyzes monounsaturated fatty acid synthesis and is transcriptionally inhibited by leptin, was also lower in IH+leptin vs. IH by Western blot (0.65±0.07 vs. 1.00±0.05 arb. units; p<0.01). In summary, we describe a novel role for leptin in protecting against IH-induced vascular stiffness and endothelial dysfunction, associated with improved dyslipidemia and reduced SCD-1 in mice. Leptin’s inhibitory actions on fatty acid synthesis may provide vascular benefits in sleep apnea and hyperlipidemia and offer new therapeutic strategies in patients with these conditions.