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

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 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.

Sleep apnea: An overlooked cause of lipotoxicity?

“…However, some studies support the concept that OSA can induce cardiometabolic dysfunction [5, 6]. Proposed causal mechanisms include over-activation of sympathetic nervous system (SNS) [7, 8], tissue hypoxia [9–11], oxidative stress [12, 13] and inflammation [14, 15]. Comparatively less attention has been directed towards changes in lipid metabolism during sleep.…”

Sleep apnoea, insulin resistance and diabetes: the first step is in the fat

“…In line with the M1 polarisation identified in adipose tissue, MURPHY et al [18] also describe that, in subjects without comorbidities, OSA severity correlates with serum levels of CD163, a surface marker characteristic of M2 macrophages, but whose soluble fraction requires M1-dependent cleavage [21]. It has therefore been considered a pro-inflammatory biomarker of several cardiovascular diseases, including insulin resistance and T2D [22].…”

“…However, although IH appears to be responsible for insulin resistance, the mechanisms involved remain unclear. The article in this issue of the European Respiratory Journal by MURPHY et al [18] provides important novel data demonstrating that IH decreases insulin sensitivity in lean and obese mice as well as cultured adipocytes, impeding insulin-mediated glucose uptake and, subsequently, inducing insulin resistance. In both murine epididymal visceral fat and adipocytes, IH down-regulates insulin-receptor substrate 1 (IRS-1) mRNA, decreasing insulin-induced tyrosine phosphorylation of the insulin receptor (IRβ) and IRS, as well as phosphorylation of Akt in adipocytes.…”

Personalized Cardio‐Metabolic Responses to an Anti‐Inflammatory Nutrition Intervention in Obese Adolescents: A Randomized Controlled Crossover Trial

“…Supernatants were collected and stored at −80 °C until analyzed. PBMC RNA isolation is described elsewhere …”

“…Saturated fatty acid (SFA)–rich high fat diets (HFD) induce IR, adipose tissue inflammation, hypertrophy, and hypoxia . In contrast, a HFD supplemented with MUFA or long chain (LC) n‐3 PUFA is associated with adipose hyperplasia and attenuated inflammation . The impact of dietary fatty acid modification on insulin sensitivity and adiponectin in overweight adolescents however is poorly understood …”