Restoring leptin signaling reduces hyperlipidemia and improves vascular stiffness induced by chronic intermittent hypoxia

Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
AJP Heart and Circulatory Physiology (Impact Factor: 3.84). 03/2011; 300(4):H1467-76. DOI: 10.1152/ajpheart.00604.2009
Source: PubMed


Chronic intermittent hypoxia (IH) during sleep can result from obstructive sleep apnea (OSA), a disorder that is particularly prevalent in obesity. OSA is associated with high levels of circulating leptin, cardiovascular dysfunction, and dyslipidemia. Relationships between leptin and cardiovascular function in OSA and chronic IH are poorly understood. We exposed lean wild-type (WT) and obese leptin-deficient ob/ob mice to IH for 4 wk, with and without leptin infusion, and measured cardiovascular indices including aortic vascular stiffness, endothelial function, cardiac myocyte morphology, and contractile properties. At baseline, ob/ob mice had decreased vascular compliance and endothelial function vs. WT mice. We found that 4 wk of IH decreased vascular compliance and endothelial relaxation responses to acetylcholine in both WT and leptin-deficient ob/ob animals. Recombinant leptin infusion in both strains restored IH-induced vascular abnormalities toward normoxic WT levels. Cardiac myocyte morphology and function were unaltered by IH. Serum cholesterol and triglyceride levels were significantly decreased by leptin treatment in IH mice, as was hepatic stearoyl-Coenzyme A desaturase 1 expression. Taken together, these data suggest that restoring normal leptin signaling can reduce vascular stiffness, increase endothelial relaxation, and correct dyslipidemia associated with IH.

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    • "Thus, the elevation of leptin levels caused by the hypoxic stress induced by IH exposure may represent an important compensatory response that acts to minimize metabolic dysfunction [9]. However, in some previous reports, SH induced higher leptin levels than IH [17], [26], and in another previous study, 5-day IH exposure elevates circulating leptin levels, but a lower leptin level observed at the 4-week time point in this study [62], which are contradictory with our results. One of the possible explanations for this discrepancy may be related to different degrees and frequencies of IH utilized in various experiments. "
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    ABSTRACT: Intermittent hypoxia (IH), resulted from recurring episodes of upper airway obstruction, is the hallmark feature and the most important pathophysiologic pathway of obstructive sleep apnea (OSA). IH is believed to be the most important factor causing systemic inflammation. Studies suggest that insulin resistance (IR) is positively associated with OSA. In this study, we hypothesized that the recurrence of IH might result in cellular and systemic inflammation, which was manifested through the levels of proinflammatory cytokines and adipokines after IH exposure, and because IR is linked with inflammation tightly, this inflammatory situation may implicate an IR status. We developed an IH 3T3-L1 adipocyte and rat model respectively, recapitulating the nocturnal oxygen profile in OSA. In IH cells, nuclear factor kappa B (NF-κB) DNA binding reactions, hypoxia-inducible factor-1α (HIF-1α), glucose transporter-1 (Glut-1), necrosis factor alpha (TNF-α), interleukin (IL) -6, leptin, adiponectin mRNA transcriptional activities and protein expressions were measured. In IH rats, blood glucose, insulin, TNF-α, IL-6, leptin and adiponectin levels were analyzed. The insulin and blood glucose levels in rats and NF-κB DNA binding activities in cells had significantly statistical results described as severe IH>moderate IH>mild IH>sustained hypoxia>control. The mRNA and protein levels of HIF-1α and Glut-1 in severe IH group were the highest. In cellular and animal models, both the mRNA and protein levels of TNF-α, IL-6 and leptin were the highest in severe IH group, when the lowest in severe IH group for adiponectin. Oxidative stress and the release of pro-inflammatory cytokines/adipokines, which are the systemic inflammatory markers, are associated with IH closely and are proportional to the severity of IH. Because IR and glucose intolerance are linked with inflammation tightly, our results may implicate the clinical relationships between OSA and IR.
    Full-text · Article · Jan 2014 · PLoS ONE
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    • "Leptin is a neuroendocrine peptide released by adipose tissue which enhances metabolism and acts on the hypothalamus suppressing appetite.[1–2] Mounting evidence suggests that, besides its central role in energy homeostasis regulation, leptin is involved in important processes in the cardiovascular system, including sympathetic activation,[3–4] angiogenesis,[5–7] and endothelial nitric oxide (NO) production.[689] "
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    ABSTRACT: Evidence suggests that leptin is involved in relevant processes in the cardiovascular system. Low serum leptin levels have been associated with increased cardiovascular events and mortality in patients with coronary artery, diabetes, or chronic kidney disease. We hypothesized that leptin is increased in pulmonary arterial hypertension (PAH) and provides prognostic information. We correlated leptin levels with clinical data and assessed its association with survival. Sixty-seven patients with PAH and 29 healthy controls were studied. Plasma leptin levels were nonlinearly associated with BMI. Leptin level <15 μg/l was associated with higher mortality in PAH patients, with an adjusted (age, gender, BMI, and smoking status) hazard ratio of 3.8 (95% CI: 1.3-11.2), P=0.016. Similarly, PAH patients with leptin/BMI ratio <0.5 μg * m(2)/kg * l had worse survival than those with a level >0.5 μg * m(2)/ kg * l (P=0.046 by log-rank test). Two-year mortality in PAH patients was 24%. A receiver operating characteristic curve using leptin/BMI ratio as the test variable and 2-year mortality as the state variable showed an area under the curve of 0.74 (95% CI: 0.62-0.86). A leptin/BMI ratio cut-off of 0.6 had a high sensitivity (94%) and negative predictive value (96%) for predicting death of any cause at 2 years. In PAH, plasma leptin levels are directly associated with BMI. Lower leptin levels, when adjusted by BMI, are associated with an increased overall mortality and leptin/BMI ratio has high negative predictive value for mortality at 2 years.
    Full-text · Article · Apr 2012

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