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

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 × 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 (p_AUC = 0.002) and elevated plasma lactate concentrations (p_AUC = 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).

Keywords: Hypoxia exposure; Inflammation; Insulin sensitivity; Obesity; RCT; Substrate metabolism.