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

R.L.J. van Meijel, M.A.A. Vogel, J.W.E. Jocken, L.M.M. Vliex, J.S.J. Smeets, N. Hoebers, J. Hoeks, Y. Essers, P.F.M. Schoffelen, H. Sell, S. Kersten, K.M.A. Rouschop, E.E. Blaak, G.H. Goossens*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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 (
Original languageEnglish
Article number101287
Number of pages13
JournalMolecular Metabolism
Publication statusPublished - 1 Nov 2021


  • Hypoxia exposure
  • Obesity
  • Insulin sensitivity
  • Substrate metabolism
  • Inflammation
  • RCT

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