title: Toll-like receptor-4 mediated inflammation is involved in the cardiometabolic alterations induced by intermittent hypoxia.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Université Grenoble Alpes, Laboratoire HP2, 38042 Grenoble, France ; INSERM U1042, 38042 Grenoble, France.
authors: Laureline
authors: 0000-0003-2137-4338
authors: L
authors: Poulain
authors: Université de Rouen, UFR Médecine-Pharmacie, 76183 Rouen, France ; INSERM U1096, 76183 Rouen, France.
authors: Vincent
authors: 0000-0003-0590-0158
authors: V
authors: Richard
authors: Université Grenoble Alpes, Laboratoire HP2, 38042 Grenoble, France ; INSERM U1042, 38042 Grenoble, France ; CHU, Hôpital A. Michallon, Laboratoires du Sommeil et EFCR, 38043 Grenoble, France.
authors: Patrick
authors: P
authors: Lévy
authors: Université Grenoble Alpes, Laboratoire HP2, 38042 Grenoble, France ; INSERM U1042, 38042 Grenoble, France ; CHU, Hôpital A. Michallon, Pôle Pluridisciplinaire de Médecine, 38043 Grenoble, France.
authors: Maurice
authors: M
authors: Dematteis
authors: Université Grenoble Alpes, Laboratoire HP2, 38042 Grenoble, France ; INSERM U1042, 38042 Grenoble, France.
authors: Claire
authors: 0000-0003-0964-9423
authors: C
authors: Arnaud
mesh_terms: D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D001011:Aorta / Q000473:pathology*; D000860:Hypoxia / Q000150:complications*; D007249:Inflammation / Q000209:etiology; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D066253:Vascular Remodeling
chemical_list: D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4