Abstract
BackgroundExperimental models of intermittent hypoxia (IH) have been developed during the last decade to investigate the consequences of obstructive sleep apnea. IH is usually associated with detrimental metabolic and vascular outcomes. However, paradoxical protective effects have also been described depending of IH patterns and durations applied in studies. We evaluated the impact of short-term IH on vascular and metabolic function in a diet-induced model of metabolic syndrome (MS).MethodsMice were fed either a standard diet or a high fat diet (HFD) for 8 weeks. During the final 14 days of each diet, animals were exposed to either IH (1 min cycle, FiO2 5% for 30s, FiO2 21% for 30s; 8 h/day) or intermittent air (FiO2 21%). Ex-vivo vascular reactivity in response to acetylcholine was assessed in aorta rings by myography. Glucose, insulin and leptin levels were assessed, as well as serum lipid profile, hepatic mitochondrial activity and tissue nitric oxide (NO) release.ResultsMice fed with HFD developed moderate markers of dysmetabolism mimicking MS, including increased epididymal fat, dyslipidemia, hepatic steatosis and endothelial dysfunction. HFD decreased mitochondrial complex I, II and IV activities and increased lactate dehydrogenase (LDH) activity in liver. IH applied to HFD mice induced a major increase in insulin and leptin levels and prevented endothelial dysfunction by restoring NO production. IH also restored mitochondrial complex I and IV activities, moderated the increase in LDH activity and liver triglyceride accumulation in HFD mice.ConclusionIn a mouse model of MS, short-term IH increases insulin and leptin levels, restores endothelial function and mitochondrial activity and limits liver lipid accumulation.
Highlights
Obesity is a rapidly growing problem that is reaching epidemic proportions worldwide, and is associated with an increased risk of cardiovascular morbidity and mortality [1, 2]
Mice fed with high fat diet (HFD) developed moderate markers of dysmetabolism mimicking metabolic syndrome (MS), including increased epididymal fat, dyslipidemia, hepatic steatosis and endothelial dysfunction
intermittent hypoxia (IH) applied to HFD mice induced a major increase in insulin and leptin levels and prevented endothelial dysfunction by restoring nitric oxide (NO) production
Summary
Obesity is a rapidly growing problem that is reaching epidemic proportions worldwide, and is associated with an increased risk of cardiovascular morbidity and mortality [1, 2]. Several clinical studies have demonstrated that NAFLD per se may constitute a cardiovascular risk factor independently of obesity and of MS components, as attested by the independent association between NAFLD and endothelial dysfunction [4, 5]. Overweight and obesity constitute the main risk factor for obstructive sleep apnea (OSA). OSA is per se recognized as an independent risk factor for cardiovascular [7] and more recently liver diseases [8]. The frequent association of OSA and obesity in clinical setting makes it difficult to investigate their independent contribution to metabolic and vascular dysfunction. Experimental models of intermittent hypoxia (IH) have been developed during the last decade to investigate the consequences of obstructive sleep apnea. We evaluated the impact of short-term IH on vascular and metabolic function in a diet-induced model of metabolic syndrome (MS)
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