The impact of mild hypoxia exposure on myokine secretion in human obesity.

BACKGROUND/OBJECTIVE: Compelling evidence indicates that myokines act in an autocrine, paracrine and endocrine manner to alter metabolic homeostasis. The mechanisms underlying exercise-induced changes in myokine secretion remain to be elucidated. Since exercise acutely decreases oxygen partial pressure (pO2) in skeletal muscle (SM), the present study was designed to test the hypothesis that (1) hypoxia exposure impacts myokine secretion in primary human myotubes and (2) exposure to mild hypoxia in vivo alters fasting and postprandial plasma myokine concentrations in humans. METHODS: Differentiated primary human myotubes were exposed to different physiological pO2 levels for 24 h, and cell culture medium was harvested to determine myokine secretion. Furthermore, we performed a randomized single-blind crossover trial to investigate the impact of mild intermittent hypoxia exposure (MIH: 7-day exposure to 15% O2, 3x2h/day vs. normoxia: 21% O2) on in vivo SM pO2 and plasma myokine concentrations in 12 individuals with overweight and obesity (body-mass index ≥ 28 kg/m2). RESULTS: Hypoxia exposure (1% O2) increased secreted protein acidic and rich in cysteine (SPARC, p = 0.043) and follistatin like 1 (FSTL1, p = 0.021), and reduced leukemia inhibitory factor (LIF) secretion (p = 0.009) compared to 3% O2 in primary human myotubes. In addition, 1% O2 exposure increased interleukin-6 (IL-6, p = 0.004) and SPARC secretion (p = 0.021), whilst reducing fatty acid binding protein 3 (FABP3) secretion (p = 0.021) compared to 21% O2. MIH exposure in vivo markedly decreased SM pO2 (≈40%, p = 0.002) but did not alter plasma myokine concentrations. CONCLUSIONS: Hypoxia exposure altered the secretion of several myokines in primary human myotubes, revealing hypoxia as a novel modulator of myokine secretion. However, both acute and 7-day MIH exposure did not induce alterations in plasma myokine concentrations in individuals with overweight and obesity. CLINICAL TRIALS IDENTIFIER: This study is registered at the Netherlands Trial Register (NL7120/NTR7325).

Effects of hypoxic exercise on 24-hour glucose profile and substrate metabolism in overweight and obese men with impaired glucose metabolism.

Hypoxic exercise (HE) may have more pronounced effects on glucose homeostasis than exercise under normoxic conditions (NE), but effects on 24-h glucose profile and substrate utilization remain unclear. We investigated the effects of moderate-intensity HE compared with NE on 24-h glucose profile and substrate metabolism in overweight/obese individuals. Ten overweight/obese men with impaired glucose homeostasis participated in a randomized, single-blind, crossover trial. Participants performed moderate-intensity cycling exercise for 4 consecutive days under mild normobaric hypoxic ([Formula: see text]: 15%) or normoxic ([Formula: see text]: 21%) conditions at similar relative exercise intensity (2 × 30 min/day at 50% of maximal heart rate, with a ∼4-wk washout period. Twenty-four-hour glucose levels and systemic oxygen saturation ([Formula: see text]) were monitored throughout the study. At day 5, plasma metabolites and substrate oxidation were determined during a mixed-meal test under normoxic conditions. [Formula: see text] and absolute workload were lower (both P < 0.001), whereas heart rate was comparable during HE compared with NE. HE did not alter mean 24-h, daytime, and nighttime glucose concentrations, and measures of glycemic variability. However, the HE-induced decrease in [Formula: see text] was positively correlated with HE-induced improvements in mean 24-h (rs = 0.683, P = 0.042) and daytime (rs = 0.783, P = 0.013) glucose concentrations. HE at similar relative exercise intensity reduces [Formula: see text] and has comparable effects on mean 24-h glucose concentration and glycemic variability than NE in overweight/obese men with impaired glucose metabolism. Nevertheless, a more pronounced reduction in [Formula: see text] during HE was associated with lower 24-h glucose concentrations, suggesting that a marked hypoxic stimulus is needed to improve glucose homeostasis.NEW & NOTEWORTHY We demonstrate that hypoxic exercise at similar relative exercise intensity (i.e. lower absolute workload) reduces systemic oxygen saturation ([Formula: see text]) and has comparable effects on mean 24-h glucose concentrations and glycemic variability than normoxic exercise in men with overweight/obesity and impaired glucose metabolism. A more pronounced reduction in [Formula: see text] during hypoxic exercise, however, was associated with lower 24-h and daytime glucose concentrations. Our findings suggest that a marked hypoxic stimulus may improve glucose homeostasis.

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

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).

The impact of hypoxia exposure on glucose homeostasis in metabolically compromised humans: A systematic review.

Humans living at a higher altitude are less prone to suffer from impaired glucose homeostasis and type 2 diabetes mellitus (T2DM), which might at least partly be explained by lower oxygen availability at higher altitudes. The present systematic review aimed to provide an overview of the current literature on the effects of hypoxia exposure on glucose homeostasis in metabolically compromised humans. Several databases were searched up to August 10th, 2020. The search strategy identified 368 unique records. Following assessment for eligibility based on the selection criteria, 16 studies were included in this review. Six studies (2 controlled studies; 4 uncontrolled studies) demonstrated beneficial effects of hypoxia exposure on glucose homeostasis, while 10 studies (8 controlled studies; 2 uncontrolled studies) reported no improvement in glucose homeostasis following hypoxia exposure. Notably, passive hypoxia exposure seemed to improve glucose homeostasis, whereas hypoxic exercise training (2-8 weeks) appeared to have no additional/synergistic effects on glucose homeostasis compared to normoxia exposure. Due to the heterogeneity in study populations and intervention duration (acute studies / 2-8 wks training), it is difficult to indicate which factors may explain conflicting study outcomes. Moreover, these results should be interpreted with some caution, as several studies did not include a control group. Taken together, hypoxia exposure under resting and exercise conditions might provide a novel therapeutic strategy to improve glucose homeostasis in metabolically compromised individuals, but more randomized controlled trials are warranted before strong conclusions on the effects of hypoxia exposure on glucose homeostasis can be drawn.

The Effects of Mild Intermittent Hypoxia Exposure on the Abdominal Subcutaneous Adipose Tissue Proteome in Overweight and Obese Men: A First-in-Human Randomized, Single-Blind, and Cross-Over Study.

Adipose tissue (AT) oxygen tension (pO2) has been implicated in AT dysfunction and metabolic perturbations in both rodents and humans. Compelling evidence suggests that hypoxia exposure alters metabolism, at least partly through effects on AT. However, it remains to be elucidated whether mild intermittent hypoxia (MIH) exposure impacts the AT proteome. We performed a randomized, single-blind, and cross-over study to investigate the effects of seven consecutive days of MIH (FiO2 15%, 3x2h/d) compared to normoxia (FiO2 21%) exposure on the AT proteome in overweight/obese men. In vivo AT insulin sensitivity was determined by the gold standard hyperinsulinemic-euglycemic clamp, and abdominal subcutaneous AT biopsies were collected under normoxic fasting conditions following both exposure regimens (day 8). AT proteins were isolated and quantified using liquid chromatography-mass spectrometry. After correction for blood contamination, 1,022 AT protein IDs were identified, of which 123 were differentially expressed following MIH (p < 0.05). We demonstrate for the first time that MIH exposure, which markedly reduces in vivo AT oxygen tension, impacts the human AT proteome. Although we cannot exclude that a single differentially expressed protein might be a false positive finding, several functional pathways were altered by MIH exposure, also after adjustment for multiple testing. Specifically, differentially expressed proteins were involved in redox systems, cell-adhesion, actin cytoskeleton organization, extracellular matrix composition, and energy metabolism. The MIH-induced change in AT TMOD3 expression was strongly related to altered in vivo AT insulin sensitivity, thus linking MIH-induced effects on the AT proteome to metabolic changes in overweight/obese humans.

Oxygenation of adipose tissue: A human perspective.

Obesity is a complex disorder of excessive adiposity, and is associated with adverse health effects such as cardiometabolic complications, which are to a large extent attributable to dysfunctional white adipose tissue. Adipose tissue dysfunction is characterized by adipocyte hypertrophy, impaired adipokine secretion, a chronic low-grade inflammatory status, hormonal resistance and altered metabolic responses, together contributing to insulin resistance and related chronic diseases. Adipose tissue hypoxia, defined as a relative oxygen deficit, in obesity has been proposed as a potential contributor to adipose tissue dysfunction, but studies in humans have yielded conflicting results. Here, we will review the role of adipose tissue oxygenation in the pathophysiology of obesity-related complications, with a specific focus on human studies. We will provide an overview of the determinants of adipose tissue oxygenation, as well as the role of adipose tissue oxygenation in glucose homeostasis, lipid metabolism and inflammation. Finally, we will discuss the putative effects of physiological and experimental hypoxia on adipose tissue biology and whole-body metabolism in humans. We conclude that several lines of evidence suggest that alteration of adipose tissue oxygenation may impact metabolic homeostasis, thereby providing a novel strategy to combat chronic metabolic diseases in obese humans.