Mild intermittent hypoxia exposure induces metabolic and molecular adaptations in men with obesity

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Abstract

Objective: Recent studies suggest that hypoxia exposure may improve glucose homeostasis, but well-controlled human studies are lacking. We hypothesized that mild intermittent hypoxia (MIH) exposure decreases tissue oxygen partial pressure (pO2) and induces metabolic improvements in people who are overweight/obese. Methods: In a randomized, controlled, single-blind crossover study, 12 men who were overweight/obese were exposed to MIH (15 % O2, 3 x 2 h/day) or normoxia (21 % O2) for 7 consecutive days. Adipose tissue (AT) and skeletal muscle (SM) pO2, fasting/postprandial substrate metabolism, tissue-specific insulin sensitivity, SM oxidative capacity, and AT and SM gene/protein expression were determined. Furthermore, primary human myotubes and adipocytes were exposed to oxygen levels mimicking the hypoxic and normoxic AT and SM microenvironments. Results: MIH decreased systemic oxygen saturation (92.0 +/- 0.5 % vs 97.1 +/- 0.3, p < 0.001, respectively), AT pO2 (21.0 +/- 2.3 vs 36.5 +/- 1.5 mmHg, p < 0.001, respectively), and SM pO2 (9.5 +/- 2.2 vs 15.4 +/- 2.4 mmHg, p = 0.002, respectively) compared to normoxia. In addition, MIH increased glycolytic metabolism compared to normoxia, reflected by enhanced fasting and postprandial carbohydrate oxidation (pAUC = 0.002) and elevated plasma lactate concentrations (pAUC = 0.005). Mechanistically, hypoxia exposure increased insulin-independent glucose uptake compared to standard laboratory conditions (-50 %, p < 0.001) and physiological normoxia (-25 %, p = 0.019) through AMP-activated protein kinase in primary human myotubes but not in primary human adipocytes. MIH upregulated inflammatory/metabolic pathways and downregulated extracellular matrix-related pathways in AT but did not alter systemic inflammatory markers and SM oxidative capacity. MIH exposure did not induce significant alterations in AT (p = 0.120), hepatic (p = 0.132) and SM (p = 0.722) insulin sensitivity. Conclusions: Our findings demonstrate for the first time that 7-day MIH reduces AT and SM pO2, evokes a shift toward glycolytic metabolism, and induces adaptations in AT and SM but does not induce alterations in tissue-specific insulin sensitivity in men who are overweight/obese. Future studies are needed to investigate further whether oxygen signaling is a promising target to mitigate metabolic complications in obesity. Clinical trial registration: This study is registered at the Netherlands Trial Register (NL7120/NTR7325). (c) 2021 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Original languageEnglish
Article number101287
Number of pages13
JournalMolecular Metabolism
Volume53
DOIs
Publication statusPublished - 1 Nov 2021

Keywords

  • Hypoxia exposure
  • Obesity
  • Insulin sensitivity
  • Substrate metabolism
  • Inflammation
  • RCT
  • TISSUE OXYGEN-TENSION
  • INSULIN SENSITIVITY
  • GLUCOSE-TOLERANCE
  • SKELETAL-MUSCLE
  • RESVERATROL SUPPLEMENTATION
  • OXIDATION
  • TRANSCRIPTION
  • MACROPHAGES
  • EXPRESSION
  • RESISTANCE

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