Abstract
Adipose tissue (AT) oxygen tension (pO2) has been implicated in AT dysfunction and metabolic perturbations in both rodents and humans. Compelling evidence suggests that hypoxia exposure alters metabolism, at least partly through effects on AT. However, it remains to be elucidated whether mild intermittent hypoxia (MIH) exposure impacts the AT proteome. We performed a randomized, single-blind, and cross-over study to investigate the effects of seven consecutive days of MIH (FiO2 15%, 3x2h/d) compared to normoxia (FiO2 21%) exposure on the AT proteome in overweight/obese men. In vivo AT insulin sensitivity was determined by the gold standard hyperinsulinemic-euglycemic clamp, and abdominal subcutaneous AT biopsies were collected under normoxic fasting conditions following both exposure regimens (day 8). AT proteins were isolated and quantified using liquid chromatography-mass spectrometry. After correction for blood contamination, 1,022 AT protein IDs were identified, of which 123 were differentially expressed following MIH (p < 0.05). We demonstrate for the first time that MIH exposure, which markedly reduces in vivo AT oxygen tension, impacts the human AT proteome. Although we cannot exclude that a single differentially expressed protein might be a false positive finding, several functional pathways were altered by MIH exposure, also after adjustment for multiple testing. Specifically, differentially expressed proteins were involved in redox systems, cell-adhesion, actin cytoskeleton organization, extracellular matrix composition, and energy metabolism. The MIH-induced change in AT TMOD3 expression was strongly related to altered in vivo AT insulin sensitivity, thus linking MIH-induced effects on the AT proteome to metabolic changes in overweight/obese humans.
Highlights
The prevalence of obesity has increased drastically over the last decades, with nearly a third of the world’s population living with overweight or obesity (Chooi et al, 2019)
We investigated the impact of mild intermittent hypoxia (MIH) compared to normoxia exposure on the abdominal subcutaneous adipose tissue (AT) proteome in overweight and obese men, using untargeted liquid chromatography-mass spectrometry, to elucidate the physiological and functional adaptations in human AT evoked by MIH
Single-blind, and cross-over study, we examined for the first time the effects of 7 consecutive days of MIH compared to normoxia exposure on the abdominal subcutaneous AT proteome in overweight and obese men
Summary
The prevalence of obesity has increased drastically over the last decades, with nearly a third of the world’s population living with overweight or obesity (Chooi et al, 2019). AT oxygen tension (pO2) has been implicated in AT dysfunction in both rodents and humans, as reviewed recently (Lempesis et al, 2020). AT hypoxia has been consistently shown in rodent models of obesity, conflicting findings have been reported in humans (Lempesis et al, 2020). We have previously demonstrated higher AT pO2 in obese compared to lean individuals (Goossens et al, 2011), decreased AT pO2 following diet-induced weight loss (Vink et al, 2017), and a positive association between AT pO2 and insulin resistance in humans, independently of adiposity (Goossens et al, 2018). Hypoxia exposure appears to have profound effects on mRNA expression of several genes related to glucose and lipid metabolism in murine and human adipocytes, as reviewed extensively (Trayhurn, 2013; Lempesis et al, 2020). The physiological effects of hypoxia are largely dependent upon the severity (mild versus severe), frequency (chronic versus intermittent), and duration (short versus long-term) of exposure (Navarrete-Opazo and Mitchell, 2014; Lempesis et al, 2020)
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