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

Molecular Metabolism

Henrike Sell¹  Gijs H. Goossens²  Paul F.M. Schoffelen²  Rens L.J. van Meijel²  Joey S.J. Smeets²  Max A.A. Vogel²  Johan W.E. Jocken²  Nicole Hoebers²  Yvonne Essers²  Lars M.M. Vliex²  Joris Hoeks³  Ellen E. Blaak⁴  Kasper M.A. Rouschop⁵  Sander Kersten⁶ 

[1] Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, the Netherlands;Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, the Netherlands;Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, the Netherlands;Maastricht Radiation Oncology (MaastRO) Laboratory, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, the Netherlands;Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, the Netherlands;Paul-Langerhans-Group for Integrative Physiology, German Diabetes Center, Dusseldorf, Germany;

关键词: Hypoxia exposure;    Obesity;    Insulin sensitivity;    Substrate metabolism;    Inflammation;    RCT;   

DOI  :  

来源: DOAJ

【 摘 要 】

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 × 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).

【 授权许可】

Unknown