Abstract
Although acute exposure to hypoxia can disrupt metabolism, longer-term exposure may normalize glucose homeostasis or even improve glucose disposal in the presence of obesity. We examined the effects of two-week exposure to room air (Air), continuous 10% oxygen (C10%), and 12 hr nocturnal periods of 10% oxygen (N10%) on glucose disposal, insulin responsiveness, and mitochondrial function in lean and obese C57BL/6J mice. Both C10% and N10% improved glucose disposal relative to Air in lean and obese mice without evidence of an increase in insulin responsiveness; however, only the metabolic improvements with N10% exposure occurred in the absence of confounding effects of weight loss. In lean mice, N10% exposure caused a decreased respiratory control ratio (RCR) and increased reactive oxygen species (ROS) production in the mitochondria of the muscle and liver compared to Air-exposed mice. In the absence of hypoxia, obese mice exhibited a decreased RCR in the muscle and increased ROS production in the liver compared to lean mice; however, any additional effects of hypoxia in the presence of obesity were minimal. Our data suggest that the development of mitochondrial inefficiency may contribute to metabolic adaptions to hypoxia, independent of weight, and metabolic adaptations to adiposity, independent of hypoxia.
Highlights
Hypoxia is a common consequence of pathology or disease, and induces adaptive physiologic responses with altitude exposure [1, 2]
We have shown that four weeks of sustained hypoxia in lean mice, simulating altitude exposure, improves glucose disposal relative to four weeks of intermittent hypoxia, simulating obstructive sleep apnea [14]
Given that mitochondria are impacted by both obesity [24] and hypoxia [25, 26], we examined the metabolic effects of diet-induced obesity and sustained hypoxic exposure on whole body glucose disposal and insulin responsiveness, and mitochondrial function of the muscle and liver in C57BL/6J mice fed either a regular chow or high-fat diet and exposed to continuous or nocturnal hypoxia for two weeks
Summary
Hypoxia is a common consequence of pathology or disease, and induces adaptive physiologic responses with altitude exposure [1, 2]. Hypoxia can occur in cells, tissues, and organs and manifest as intermittent or sustained in nature [3]. Short-term exposure to altitude hypoxia can induce acute mountain sickness [11], whereas adaptation occurs over days to weeks at altitude [12, 13]. We have shown that four weeks of sustained hypoxia in lean mice, simulating altitude exposure, improves glucose disposal relative to four weeks of intermittent hypoxia, simulating obstructive sleep apnea [14]. Studies of high-altitude natives provide biologic plausibility for chronic altitude exposure to improve glucose metabolism [15, 16], and, experimentally, ten nights of moderate hypoxic
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