Chronic Intermittent Hypoxia Induces Early-Stage Metabolic Dysfunction Independently of Adipose Tissue Deregulation.

Ana Obeso,Jesus Prieto-Lloret,Fátima O. Martins,Elena Olea,Joana F. Sacramento,Emilia C. Monteiro,Silvia V. Conde,Bernardete F. Melo,Paulo Matafome,Asuncion Rocher

doi:10.3390/antiox10081233

Abstract

Several studies demonstrated a link between obstructive sleep apnea (OSA) and the development of insulin resistance. However, the main event triggering insulin resistance in OSA remains to be clarified. Herein, we investigated the effect of mild and severe chronic intermittent hypoxia (CIH) on whole-body metabolic deregulation and visceral adipose tissue dysfunction. Moreover, we studied the contribution of obesity to CIH-induced dysmetabolic states. Experiments were performed in male Wistar rats submitted to a control and high-fat (HF) diet. Two CIH protocols were tested: A mild CIH paradigm (5/6 hypoxic (5% O2) cycles/h, 10.5 h/day) during 35 days and a severe CIH paradigm (30 hypoxic (5% O2) cycles, 8 h/day) during 15 days. Fasting glycemia, insulinemia, insulin sensitivity, weight, and fat mass were assessed. Adipose tissue hypoxia, inflammation, angiogenesis, oxidative stress, and metabolism were investigated. Mild and severe CIH increased insulin levels and induced whole-body insulin resistance in control animals, effects not associated with weight gain. In control animals, CIH did not modify adipocytes perimeter as well as adipose tissue hypoxia, angiogenesis, inflammation or oxidative stress. In HF animals, severe CIH attenuated the increase in adipocytes perimeter, adipose tissue hypoxia, angiogenesis, and dysmetabolism. In conclusion, adipose tissue dysfunction is not the main trigger for initial dysmetabolism in CIH. CIH in an early stage might have a protective role against the deleterious effects of HF diet on adipose tissue metabolism.

Highlights

We provided mechanistic insights showing that both mild and severe chronic intermittent hypoxia (CIH) prompted whole-body insulin resistance and hyperinsulinemia, these early dysmetabolic states are not associated with increased weight gain, adipocytes perimeter, adipose tissue hypoxia, and inflammation or oxidative stress
Insulin sensitivity, given by the HOMA-IR, decreased in the animals exposed to both CIH paradigms, since the HOMA-IR values increased by 130 and 94% with mild and severe CIH, respectively (Table 1)
We show that neither mild CIH (Appendix A Figure A1) nor 2 weeks of severe CIH (Figure 5) produced a pro-inflammatory profile within the visceral adipose tissue assessed by measuring the levels of expression of the receptors of pro-inflammatory molecules—TNF-α, IL1, and IL6, through the expression of enzymes—iNOS and transcription factors—NFkB, IkBα involved in inflammatory pathways

Summary

Introduction

Obstructive sleep apnea (OSA), the most common sleep disorder, is characterized by repetitive episodes of airflow cessation (apnea) or airflow reduction (hypopnea) caused by an obstructed or collapsed upper airway during sleep, which results in intermittent hypoxemia and hypercapnia. It is estimated that 1 billion adults aged 30–69 years worldwide could have OSA [1]. Several studies have described the relationship between OSA and metabolic diseases. Intermittent hypoxia and sleep fragmentation lead to insulin resistance, type 2 diabetes, metabolic syndrome, and aggravates obesity [2]

Methods

Results

Conclusion