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.
Intermittent hypoxia induces inflammatory phenotype of adipose tissue leading to insulin resistance in sleep apnoea http://ow.ly/k1TX3091YBM
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Support statement: This work was supported by the Health Research Board of Ireland (S. Ryan), the Science Foundation of Ireland (H.M. Roche and A.M. Murphy) and by Agir pour les maladies chroniques (J-L. Pepin). The murine studies were partly supported by the French National Research Agency in the framework of the “Investissements d’avenir” programme (ANR-15-IDEX-02). Funding information for this article has been deposited with the Crossref Funder Registry.
Conflict of interest: None declared.
- Received August 31, 2016.
- Accepted December 20, 2016.
- Copyright ©ERS 2017