Elsevier

Molecular Metabolism

Volume 53, November 2021, 101287
Molecular Metabolism

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

https://doi.org/10.1016/j.molmet.2021.101287Get rights and content
Under a Creative Commons license
open access

Highlights

  • MIH exposure decreases oxygen partial pressure in human adipose tissue and skeletal muscle.

  • MIH exposure induces a shift in substrate utilization toward glycolytic metabolism.

  • Hypoxia exposure increases insulin-independent glucose uptake in primary human myotubes, at least in part through AMPK.

  • MIH does not alter adipose tissue, hepatic and peripheral insulin sensitivity.

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 (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).

Keywords

Hypoxia exposure
Obesity
Insulin sensitivity
Substrate metabolism
Inflammation
RCT

Cited by (0)

6

Rens L.J. van Meijel and Max A.A. Vogel contributed equally to this work.

7

Deceased.