Intermittent hypoxia in obstructive sleep apnoea mediates insulin resistance through adipose tissue inflammation

Aoife Murphy, Amandine Thomas, Sophie Crinion, Brian Kent, Murtaza Tambuwala, Aurelie Fabre, Jean-Louis PEPIN, Helen Roche, Claire ARNAUD, Silke Ryan

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Obstructive sleep apnoea (OSA) is increasingly associated with insulin resistance. The underlying pathophysiology remains unclear but intermittent hypoxia (IH)-mediated inflammation and subsequent dysfunction of the adipose tissue has been hypothesised to play a key role.We tested this hypothesis employing a comprehensive translational approach using a murine IH model of lean and diet-induced obese mice, an innovative IH system for cell cultures and a tightly controlled patient cohort.IH led to the development of insulin resistance in mice, corrected for the degree of obesity, and reduced insulin-mediated glucose uptake in 3T3-L1 adipocytes, associated with inhibition of the insulin-signalling pathway and downregulation of insulin-receptor substrate-1 mRNA. Providing mechanistic insight, IH induced a pro-inflammatory phenotype of visceral adipose tissue in mice with pro-inflammatory M1 macrophage polarisation correlating with the severity of insulin resistance. Complimentary in vitro analysis demonstrated that IH led to M1 polarisation of THP1-derived macrophages. In subjects without comorbidities (n=186), OSA was independently associated with insulin resistance. Furthermore, we found an independent correlation of OSA severity with the M1 macrophage inflammatory marker sCD163.This study provides evidence that IH induces a pro-inflammatory phenotype of the adipose tissue,which may be a crucial link between OSA and the development of insulin resistance.
Original languageEnglish
Pages (from-to)1-11
Number of pages11
JournalEuropean Respiratory Journal
Volume49
Early online date19 Apr 2017
DOIs
Publication statusE-pub ahead of print - 19 Apr 2017

Keywords

  • obstructive sleep apnea
  • intermittent hypoxia
  • insulin resistance
  • adipose
  • tissue inflammation

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