Intermittent Hypoxia Mediates Caveolae Disassembly That Parallels Insulin Resistance Development.

Maider Varela-Guruceaga,Soazig Le Lay,Ella Aka,Ramaroson Andriantsitohaina,Lucie Lebeau,Elise Belaidi,Claire Arnaud,Sophie Giorgetti-Peraldi

doi:10.3389/fphys.2020.565486

Abstract

Repetitive complete or incomplete pharyngeal collapses are leading to chronic intermittent hypoxia (CIH), a hallmark feature of obstructive sleep apnea (OSA) syndrome responsible for many metabolic disorders. In humans, an association between OSA and insulin resistance has been found independently of the degree of obesity. Based on our previous work showing that hypoxia applied to adipocytes led to cellular insulin resistance associated with caveolae flattening, we have investigated the effects of CIH on caveolae structuration in adipose tissue. Original exploratory experiences demonstrate that 6 weeks-exposure of lean mice to CIH is characterized by systemic insulin resistance and translates into adipocyte insulin signaling alterations. Chronic intermittent hypoxia also induces caveolae disassembly in white adipose tissue (WAT) illustrated by reduced plasma membrane caveolae density and enlarged caveolae width, concomitantly to WAT insulin resistance state. We show that CIH downregulates caveolar gene and protein expressions, including cavin-1, cavin-2, and EHD2, underlying molecular mechanisms responsible for such caveolae flattening. Altogether, we provide evidences for adipose tissue caveolae disassembly following CIH exposure, likely linked to cavin protein downregulation. This event may constitute the molecular basis of insulin resistance development in OSA patients.

Highlights

Obstructive sleep apnea (OSA) is characterized by frequent episodes of partial or complete upper airway obstructions during sleep leading to repetitive apneas and hypopneas (Levy et al, 2015)
Hypoxia within the adipose tissue was monitored by the increased expression of REDD1, a hypoxia-inducible protein that has been demonstrated to be involved in metabolic disorders (Regazzetti et al, 2015)
Whereas 6 weeks chronic intermittent hypoxia (CIH) exposure has no significant impact on mice total body weight nor on adiposity or adipocyte size (Table 1), we confirmed that long-term exposure to CIH increased HOmeostatic model assessment of insulin resistance (HOMA-IR) (1.05 ± 0.2 and 2.9 ± 0.5, in N and CIH respectively, p < 0.05 versus N) showing that CIH induces systemic insulin resistance

Summary

Introduction

Obstructive sleep apnea (OSA) is characterized by frequent episodes of partial or complete upper airway obstructions during sleep leading to repetitive apneas and hypopneas (Levy et al, 2015). Repetitive airway pharyngeal collapses lead to chronic intermittent hypoxia (CIH), a hallmark feature of OSA responsible for metabolic disorders. Intermittent Hypoxia Mediates Caveolae Disassembly including cardiovascular co-morbidities, metabolic syndrome and type 2 diabetes (Levy et al, 2015). Clinical studies have established an independent association between OSA and insulin resistance, independently of the degree of obesity (Ip et al, 2002; Fredheim et al, 2011; Murphy et al, 2017). Mimicking OSA in rodents by exposing animals to repetitive hypoxia/reoxygenation cycles confirms the causal link between CIH, systemic insulin resistance and insulin signaling alterations in white adipose tissue (WAT), independently of obesity (Murphy et al, 2017; Thomas et al, 2017). Possible mechanisms underlying insulin resistance development includes CIH-induced HIF-1 (hypoxia inducible factor-1) activation, the master regulator of oxygen homeostasis (Belaidi et al, 2016; Khalyfa et al, 2017)

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