Intermittent hypoxia in obese Zucker rats: cardiometabolic and inflammatory effects

Abstract

What is the central question of this study? This study addresses the relative impact of obesity and intermittent hypoxia in the pathophysiological process of obstructive sleep apnoea by investigating the metabolic, inflammatory and cardiovascular consequences of intermittent hypoxia in lean and obese Zucker rats. What is the main finding and its importance? We found that obesity and intermittent hypoxia have mainly distinct consequences on the investigated inflammatory and cardiometabolic parameters in Zucker rats. This suggests that, for a given severity of sleep apnea, the association of obesity and obstructive sleep apnoea may not necessarily be deleterious. Obstructive sleep apnoea is associated with obesity with a high prevalence, and both co-morbidities are independent cardiovascular risk factors. Intermittent hypoxia (IH) is thought to be the main factor responsible for the obstructive sleep apnoea-related cardiometabolic alterations. The aim of this study was to assess the respective impact of obesity and IH on the inflammatory and cardiometabolic state in rats. Lean and obese Zucker rats were exposed to normoxia or chronic IH, and we assessed metabolic and inflammatory parameters, such as plasma lipids and glucose, serum leptin and adiponectin, liver cytokines, nuclear factor-κB activity and cardiac endothelin-1 levels. Myocardial infarct size was also evaluated following in vitro ischaemia-reperfusion. Circulating lipids, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), leptin and adiponectin levels were higher in obese versus lean rats. Chronic IH did not have a significant impact on metabolic parameters in lean rats. In obese rats, IH increased glycaemia and HOMA-IR. Liver interleukin-6 and tumour necrosis factor-α levels were elevated in lean rats exposed to IH; obesity prevented the increase in interleukin-6 but not in tumour necrosis factor-α. Finally, IH exposure enhanced myocardial sensitivity to infarction in both lean and obese rats and increased cardiac endothelin-1 in lean but not obese rats. In conclusion, this study shows that the dyslipidaemia and insulin resistance induced by obesity of genetic origin does not enhance the deleterious cardiovascular response to IH and may even partly protect against IH-induced inflammation.

Sustained Intermittent Hypoxemia Induces Adiponectin Oligomers Redistribution and a Tissue-Specific Modulation of Adiponectin Receptor in Mice

“…In addition to the type of hypoxemia, the duration of exposure is another parameter that could influence Ad circulating levels. Indeed, previous studies did not find any modification of Ad levels in rats submitted to intermittent or continuous hypoxia for 14 days, as well as in mice exposed to hypoxia for 21 days (Chaiban et al, 2008; van den Borst et al, 2013; Briançon-Marjollet et al, 2016). By contrast, after 8 weeks of exposure to continuous hypoxia (FiO 2 : 10%, 24 h/day), Chaiban et al (2008) observed an increased Ad level in hypoxemic mice.…”

Pathogenesis of Abnormal Hepatic Lipid Metabolism Induced by Chronic Intermittent Hypoxia in Rats and the Therapeutic Effect of N-Acetylcysteine

“…This phenomenon can be attributed to an increased accumulation and intake of lipids due to inflammation in various organs and tissues, including the liver; alternatively, it might also be due to reduced activity and energy consumption. Obesity complicated by OSA has a high prevalence [ 23 ], although studies on the mechanism of obesity and OSA are relatively rare. St-Onge and Shechter suggested that frequent short sleep duration was the main manifestation in OSA patients due to frequent intermittent hypoxia that reduced sleep quality, leading to energy imbalance in the body and weight gain [ 24 ].…”

Leptin and Leptin Resistance in the Pathogenesis of Obstructive Sleep Apnea: A Possible Link to Oxidative Stress and Cardiovascular Complications

“…In lean mice, all types of hypoxia induced insulin resistance and increased circulating leptin levels, but only frequent IH (60 times/h) increased lipid peroxidation and TNF- α production by adipose tissue [ 72 ]. However, two weeks' exposure to IH did not increase serum leptin levels in both lean and obese Zucker rats [ 73 ], whereas leptin was upregulated by 2–5 weeks of IH in nonobese or diet-induced obese rats [ 74 , 75 ]. Such discrepancy in the results indicates that that hyperleptinemia in OSA might be modulated by severity and duration of IH and its interactions with an obese phenotype.…”