RESUMO
OBJECTIVE: Intermittent hypoxia (IH) is a major component of sleep apnea syndrome as its cardiometabolic complications have been mainly attributed to IH. The pathophysiology is still poorly understood but there are some similarities with the obesity-associated cardiometabolic complications. As the latter results from inflammation involving toll-like receptor-4 (TLR4) signaling, we assessed this pathway in the cardiometabolic consequences of IH. METHODS: Lean adult male TLR4-deficient (TLR4(-/-)) mice and their controls (C57BL/6 mice) were exposed to either IH (FiO2 21-5%, 1 min cycle, 8 h/day) or air (normoxic mice) for 4 weeks. Animals were assessed at 1-week exposure for insulin tolerance test and after 4-week exposure for morphological and inflammatory changes of the epididymal fat and thoracic aorta. RESULTS: IH induced insulin resistance, morphological and inflammatory changes of the epididymal fat (smaller pads and adipocytes, higher release of TNF-α and IL-6) and aorta (larger intima-media thickness and higher NFκB-p50 activity). All these alterations were prevented by TLR4 deletion. CONCLUSION: IH induces metabolic and vascular alterations that involve TLR4 mediated inflammation. These results confirm the important role of inflammation in the cardiometabolic consequences of IH and suggest that targeting TLR4/NFκB pathway could represent a further therapeutic option for sleep apnea patients.
Assuntos
Aorta/patologia , Hipóxia/complicações , Resistência à Insulina , Receptor 4 Toll-Like/fisiologia , Tecido Adiposo/patologia , Animais , Inflamação/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/fisiologia , Transdução de Sinais , Remodelação VascularRESUMO
Obstructive sleep apnoea is a highly prevalent disease characterised by repetitive upper airway collapse during sleep leading to intermittent hypoxia. Cardiometabolic complications of sleep apnoea have been mostly attributed to intermittent hypoxia. These consequences could be mediated through intermittent hypoxia-related alterations of the visceral white fat, as it is recognised for playing an important role in inflammation, atherogenesis and insulin resistance. Epididymal adipose tissue alterations were investigated in 20-week-old nonobese male apolipoprotein E-deficient mice exposed to intermittent hypoxia (inspiratory oxygen fraction 5-21%, 60-s cycle, 8 h · day(-1)) or air for 6 weeks. These adipose tissue alterations, as well as metabolic alterations and aortic atherosclerosis, were then assessed in lipectomised or sham-operated mice exposed to intermittent hypoxia or air for 6 weeks. Intermittent hypoxia induced morphological (shrunken adipocytes), functional (increased uncoupling protein-1 expression) and inflammatory (increased macrophage recruitment and secretion of interleukin-6 and tumour necrosis factor-α) remodelling of epididymal adipose tissue. Hypoxic mice presented more severe dyslipidaemia and atherosclerosis lesions and developed insulin resistance. Epididymal lipectomy attenuated both intermittent hypoxia-induced dyslipidaemia and atherogenesis, but did not improve insulin sensitivity. Our results confirmed that the dyslipidaemic and proatherogenic effects of intermittent hypoxia are partly mediated through morphological, functional and inflammatory remodelling of visceral white fat, regardless of obesity.
Assuntos
Tecido Adiposo Branco/patologia , Aterosclerose/patologia , Hipóxia , Gordura Intra-Abdominal/patologia , Animais , Aorta/patologia , Quimiocina CCL2/metabolismo , Teste de Tolerância a Glucose , Inflamação , Resistência à Insulina , Canais Iônicos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/metabolismo , Proteína Desacopladora 1RESUMO
Sleep apnea syndrome is characterized by repetitive upper airway collapses during night leading to intermittent hypoxia (IH). The latter is responsible for metabolic disturbances that rely, at least in part, on abdominal white fat inflammation. Besides qualitative alterations, we hypothesized that IH could also modify body fat distribution, a key factor for metabolic complications. C57BL6 mice exposed to IH (21-5% FiO2, 60 s cycle, 8 h/day) or air for 6 weeks were investigated for topographic fat alterations (whole-body MRI). Specific role of epididymal fat in IH-induced metabolic dysfunctions was assessed in lipectomized or sham-operated mice exposed to IH or air. Whereas total white fat volume was unchanged, IH induced epididymal adipose tissue (AT) loss with non-significant increase in subcutaneous and mesenteric fat. This was associated with impaired insulin sensitivity and secretion. Epididymal lipectomy led to increased subcutaneous fat in the perineal compartment and prevented IH-induced metabolic disturbances. IH led to reduced epididymal AT and impaired glucose regulation. This suggests that, rather than epididymal AT volume, qualitative fat alterations (i.e. inflammation) could represent the main determinant of metabolic dysfunction. This deterioration of glucose regulation was prevented in epididymal-lipectomized mice, possibly through prevention of IH-induced epididymal AT alterations and compensatory increase in subcutaneous AT.
Assuntos
Tecido Adiposo Branco/anatomia & histologia , Distribuição da Gordura Corporal , Hipóxia/patologia , Resistência à Insulina , Síndromes da Apneia do Sono/patologia , Animais , Modelos Animais de Doenças , Epididimo/patologia , Masculino , Camundongos Endogâmicos C57BL , Peritônio/patologia , Pele/patologiaRESUMO
RATIONALE: Obstructive sleep apnea results in nocturnal intermittent hypoxia (IH) as a main trigger for cardiovascular morbidity, including atherosclerosis. IH induces hemodynamic, hormono-metabolic and also immuno-inflammatory alterations that could differentially contribute to atherosclerosis. Our study aimed at examining their respective contribution to the proatherogenic role of IH in atherosclerosis-prone mice. METHODS: Fifteen-week-old male apolipoprotein E-deficient (ApoE(-/-)) mice fed on a high-cholesterol diet (HCD) for 6 weeks and exposed for the last 14 days to IH (21-5% FiO(2), 60s cycle, 8h/day) or air, were investigated for aortic atherosclerosis and lipid alterations. Then IH proatherogenicity was assessed in 15- and 20-week-old ApoE(-/-) mice fed on a standard-chow diet (SCD) exposed to IH or air for 14 days and assessed for atherosclerosis, lipid, hemodynamic and inflammation alterations. RESULTS: IH aggravated atherosclerosis in HCD-fed mice, whereas the extremely high cholesterol levels due to HCD were not different between normoxic and hypoxic animals. In SCD-fed mice, IH also aggravated atherosclerosis, more severely in 20 compared to 15-week-old animals. However, cholesterol levels that increased with IH were not different in the two SCD-fed groups. IH slightly elevated arterial blood pressure in 20-week-old animals only, and induced systemic and vascular inflammation, including increased splenocyte proliferation with decreased IL-10 secretion, and increased T-lymphocytes within atherosclerotic plaques. CONCLUSIONS: A short IH exposure without HCD has proatherogenic effects. In contrast to blood pressure or plasma lipids which were slightly or inconstantly affected by IH, inflammation at systemic and vascular levels appears as a potential contributing factor to IH atherogenicity.