Differential effects of intermittent hypoxia on systemic and adipose tissue inflammation in lean and diet-induced obese mice

Abstract

Background: Obstructive sleep apnoea and obesity are increasingly associated with insulin resistance. The underlying pathophysiology remains unclear but inflammation of the adipose tissue has been proposed to play an important role. The main aim of this study was to investigate the effects of acute (7 days) or chronic (4 weeks) intermittent hypoxia (IH), a hallmark of obstructive sleep apnoea, on adipose tissue inflammation in lean and diet-induced obese mice. Methods: Mice (C57BL/6J, age 4 weeks, n=6-8 in each group) were fed a regular or high-fat diet for 9 weeks and then exposed to IH (cycles of 10% O2 for 60 seconds followed by another 60 seconds of 21% O2, 30 hypoxic events per hour, 8 hours per day; BioSpherix Quick & Quiet O2 Profiler with A84XOV OxyCycler, Parish [NY], US) or room air as controls for 1 or 4 weeks. At the end of the exposure, fasting blood samples, anterior subcutaneous adipose tissue (SAT) and epididymal visceral adipose tissue (VAT) were collected after sacrifice. Serum and adipose tissue inflammatory markers such as monocyte chemoattractant protein-1 (MCP-1/CCL2), interleukin (IL)-6, and tumour necrosis factor (TNF)-α were measured. Results: Compared with lean mice, diet-induced obese mice had higher serum levels of free fatty acid and malondialdehyde, markers of oxidative stress, and MCP-1, a marker of inflammation. However, lean mice under IH caused significant elevation of serum free fatty acid and malondialdehyde levels after 1 week or 4 weeks of exposure, and serum MCP-1 only after 4 weeks of exposure compared with air-exposed group. Dietinduced obese mice showed no IH impact on those serum markers. High-fat diet induced a pro-inflammatory phenotype of SAT and VAT through upregulation of MCP-1, IL-6, and TNF-α. The IH caused elevation of MCP-1, IL-6 and TNF-α in SAT and VAT in lean mice but not in diet-induced obese mice after either 1 week or 4 weeks of exposure. Conclusion: The current experimental setting of IH increases systemic and adipose tissue inflammation in lean mice but does not pose an additional factor to inflammation in diet-induced obesity.