Review Article | Open Access
Effects of Hyperoxia on Oxygen-Related Inflammation with a Focus on Obesity
Several studies have shown a pathological oxygenation (hypoxia/hyperoxia) on the adipose tissue in obese subjects. Additionally, the excess of body weight is often accompanied by a state of chronic low-degree inflammation. The inflammation phenomenon is a complex biological response mounted by tissues to combat injurious stimuli in order to maintain cell homeostasis. Furthermore, it is believed that the abnormal oxygen partial pressure occurring in adipose tissue is involved in triggering inflammatory processes. In this context, oxygen is used in modern medicine as a treatment for several diseases with inflammatory components. Thus, hyperbaric oxygenation has demonstrated beneficial effects, apart from improving local tissue oxygenation, on promoting angiogenesis, wound healing, providing neuroprotection, facilitating glucose uptake, appetite, and others. Nevertheless, an excessive hyperoxia exposure can lead to deleterious effects such as oxidative stress, pulmonary edema, and maybe inflammation. Interestingly, some of these favorable outcomes occur under high and low oxygen concentrations. Hereby, we review a potential therapeutic approach to the management of obesity as well as the oxygen-related inflammation accompanying expanded adipose tissue, based on elevated oxygen concentrations. To conclude, we highlight at the end of this review some areas that need further clarification.
Obesity is caused by an imbalance between energy intake and energy expenditure that results in an enlarged growth in adipose tissue that is generally harmful to health . This burden of obesity on health extends across multiple organ systems and diseases  since excessive fat deposition is related to a higher prevalence of cardiovascular disease, metabolic syndrome features, different type of cancers, and other adverse clinical conditions . In addition, obesity has been associated with higher mortality rates .
In the last half century, the prevalence of human obesity has risen dramatically all over the world . High-income countries are not the only ones affected by the epidemic, as the condition is achieving alarming rates in the transition world as well . Thus, it has been reported that prevalence of obesity has almost doubled from 6.4% in 1980 to 12.0% in 2008 in the entire world. Half of this rise occurred from 2000 to 2008 . Furthermore, during 2013 worldwide obesity prevalence was estimated at 36.9% in men and 38% in women, while obesity-associated mortality and treatment expenses make this disease the major global health challenge . In addition to unhealthy habits (consumption of high-energy yielding foods and low physical activity), the interaction with genetic factors could be involved in this increased prevalence . Although human genome cannot change in such short time, mechanisms involving epigenetics have been proposed as a possible origin and/or development of this increase . Other factors have been suggested, such as microbiota, increasing maternal age, greater fecundity among obese people, assortative mating, sleep deprivation, endocrine disruptors, pharmaceutical iatrogenesis, reduction in variability of ambient temperatures, and intrauterine and intergenerational effects .
At the tissue level, obesity is known to provoke a mild but chronic inflammation state within the adipose tissue, leading to multiple metabolic disorders if the condition persists . Among the features that may lead to this inflammatory response in obesity, it has been hypothesized that poorly oxygenated adipose tissue may underlie the initiation and development of this process [12, 13], although the relationship between tissue oxygen partial pressure and adipose tissue inflammatory process is still under debate [14–16]. Regarding hypoxic conditions, several human studies have related environmental hypoxia during expeditions at moderate- and high-altitude conditions to a reduction of food intake [17, 18], subsequent metabolic alterations, and weight loss [19, 20]. Similarly, our group found that rats exposed to normobaric hypoxia reduced their food intake and, consequently, their weight . It is important to highlight that this hypobaric hypoxia differs from the hypoxia described in obese adipose tissue .
2. Inflammation and Obesity
Inflammatory processes are complex biological responses orchestrated by tissues to combat injurious stimuli, as host defense, tissue remodeling, and metabolic changes, in order to maintain cell homeostasis . More precisely, the inflammatory phenomena involve multiple specific cell processes such as recruitment and activation of immune cells (leukocytes, granulocytes, monocytes, lymphocytes, and dendritic cells), stimulation of the production of different chemical bioactive mediators (such as cytokines, chemokines, or prostanoids), regulation of signaling pathways involving insulin, leptin, glucose, or lipids, and eventually epigenetic regulation of the expression of important related genes as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB/AP1) activity or IL-6 expression [24–26]. This adaptive response can be instantaneous and short, which is known as acute inflammation, or long and gradual as in a chronic, mild inflammatory process. The latter has been established as a main cause and/or a consequence of diverse diseases that may need pharmacological interventions to attenuate the cellular inflammatory routes such as diabetes, cardiovascular diseases, and obesity .
Obesity itself is characterized by a state of mild chronic inflammation in humans . In fact, obesity-induced inflammation has been described as metaflammation, that is, a chronic and low-grade inflammatory response initiated by excess nutrients in metabolic cells, where circulating levels of an important number of inflammatory markers, such as C-reactive protein (CRP), haptoglobin, Interleukin-1 (IL-1), Interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1), or tumor necrosis factor-alpha (TNF-α), are increased [1, 29, 30]. Additional studies suggest that adipose tissue inflammatory state is orchestrated by monocyte/macrophage infiltration and overproduction of proatherogenic cytokines, two situations that are related to the initiation and development of several obesity-associated diseases such as atherosclerosis and cardiovascular complications [31–33]. Indeed, about half of the cells that make up adipose tissue of obese mice were identified as macrophages, a feature that was associated with low-grade systemic inflammation . At this point, it is important to note that there is a very specific phenotype called “Metabolically Healthy Obese (MHO),” which presents the following features: less visceral fat, less infiltration of macrophages into adipose tissue, and smaller adipocyte cell size, leading to a more favorable inflammatory profile, although a recent meta-analysis has reported that these subjects are at an increased risk of developing type 2 diabetes compared with their age-matched lean controls . In this sense, diet has a main role in the inflammation [35, 36] and oxidative stress-related outcomes [37, 38].
Certainly, several signaling pathways have been proposed to explain the cause for the initiation of inflammatory processes during obesity (Figure 1), including oxidative stress , endoplasmic reticulum stress , and adipose tissue hypoxia . These features may provoke the release of reactive molecules that can interact with proteins, lipids, or DNA, causing cell damage/death and leading to nonspecific proinflammatory effects . These theories can explain some aspects of inflammation and metabolic disorders in obesity, but the link between obesity and these factors still remains elusive [13, 42].
3. Hypoxia and Inflammation in Adipose Tissue
Adipose tissue is constituted not only by adipocytes, but also by a stromavascular cell fraction, which involves leukocytes (including macrophages), T cells, and natural killer cells . Some of these cells are a dominant source of inflammatory cytokines and are, therefore, appropriate targets for the study of mechanisms underlying hypoxia-induced inflammation within this tissue [1, 44]. Inflamed tissues are often characterized by decreased oxygen availability and cells must be able to maintain viability and proper function in strongly variable microenvironments .
Indeed, hypoxia has been proposed as a key initiator of adipokine dysregulation in obesity  by inducing the expression of certain genes in adipocytes and macrophages like TNF-α, IL-1, IL-6, MCP-1, and PAI-1, macrophage migration-inhibition factor (MIF), inducible-nitric oxide synthase (iNOS), and others [41, 46–48]. Similarly, the production of vascular endothelial growth factor (VEGF) inducing a proangiogenic response is stimulated by hypoxia in human and murine adipocytes [49, 50]. Furthermore, the role of hypoxia and angiogenesis in tumor progression has been described in several studies [51, 52]. In addition, it has been reported that low O2 availability may change the expression of diverse proinflammatory molecules [44, 50, 53–56] and, also, inhibits enzymes related to lipid metabolism such as Lipoprotein lipase by upregulating angipoietin-like protein 4 (Angptl4) . Nonetheless, different behavior patterns are found depending on cellular origin, for example, human or mouse (Figure 2).
Many of the aforementioned genes have been found to be dependent on the activation of hypoxia-inducible factor-1 alpha (HIF-1α), the master transcriptional regulator of hypoxia environment [56, 58, 59], since cellular adaptation to hypoxia appears as a defense mechanism adopted by cells to conserve the optimum oxygen concentration required for vital metabolic functions , where activation of specific and important transcription factors, such as HIF-1 or NF-κB, occurs . The transcription factor HIF-1 is a heterodimer composed of an oxygen sensitive subunit HIF-1α and a constitutively expressed subunit HIF-1β [41, 61, 62]. This protein is responsible for the induction of genes that facilitate accommodation and survival from hypoxic stress . When cellular oxygen levels are normal, this protein is immediately targeted for proteasome degradation . However, under lower oxygen concentrations  and mild oxidative stress (induced with H2O2) , as in inflamed tissues, hydroxylation is inactivated, enabling the binding of CREB-Binding Protein (CBP/p300) coactivator, and therefore HIF-1α becomes stable, leading to the expression of HIF-1 target genes. Several studies have described an increase in HIF-1α expression and protein levels in the adipose tissue of dietary obese mice and ob/ob obese mice, which are thought to suffer a low oxygen supply [3, 48]. Moreover, human primary preadipocyte cultures have shown higher levels of HIF-1α mRNA and protein than mature adipocytes . These results suggest a posttranslational regulation, where HIF-1α protein increases independently of mRNA level in response to hypoxia in adipose tissue. Interestingly, in human primary adipocytes, an elevation of HIF-1α mRNA and protein levels has been described after 8 and 24 h of hypoxic exposure . Other studies observed an enhancement of Hif-1α mRNA and protein levels in 3T3-L1 cells during adipogenesis [3, 66], whereas mRNA levels of Hif-1α did not change in an assay performed in 3T3-L1 cells under these conditions .
Although these changes are consistent with hypoxia, they are not necessarily a direct response to low oxygen concentrations, since other factors such as reactive oxygen species (ROS) production and/or endoplasmic reticulum stress are likely involved . Furthermore, another scientific group has suggested that, despite lower adipose tissue blood flow, human adipose tissue may suffer hyperoxia in obese subjects, explained apparently by lower oxygen consumption within this organ , although this needs to be further elucidated.
4. Treatments with Hyperoxia
Hyperoxia is referred to as a potentially harmful major lifesaver . Thus, oxygen is used in current medicine as a treatment for several diseases such as chronic obstructive pulmonary diseases, management of ulcers in diabetic patients, and cerebral ischemia wounds and hypothesized and studied as a tool for weight management [46, 68, 69]. Nevertheless, an excess of the exposure to oxygen in time and/or concentration may lead to important deleterious effects [70, 71].
Hyperoxia increases the amount of dissolved oxygen in blood with the subsequent action on tissue oxygenation and mitochondrial metabolism . These mechanisms explain why oxygen is used as a therapy to optimize oxygen transport capacity . There are two clearly defined therapies commonly used at the clinical level: hyperbaric oxygen therapy (HBOT) and normobaric oxygen therapy (NBOT). The former involves the inhalation of 100% O2 in a chamber at pressure greater than at sea level , while the latter involves administering more than 21% O2 at normal atmospheric pressure.
Over the past years, multiple studies have documented NBOT and HBOT to have important clinical applications (see the following).
Experimental and nonapproved claimed beneficial effects of hyperoxia treatment are as follows: Anti-inflammatory effect . Better control of blood glucose levels . Cytoprotection in chemotherapy side effects . Decreased inflammatory pain . Decreased ischemic stroke mortality and comorbidities [79–81]. Enhanced survival and regeneration of fat grafting . Improved glucose utilization by the brain . Increased angiogenesis . Increased insulin sensitivity . Neuroprotection in hypoxic-ischemic injury [86, 87]. Neuroprotection in traumatic brain injury . Terminated migraine headache pain . Tumour control and decreased mortality and recurrence . Wound healing [91–94].For example, oxygen therapy has demonstrated effectiveness in the treatment of acutely ischemic brain tissue, in acute ischemic stroke, in the amelioration of pathological brain infarct volumes, and in the enhanced survival and regeneration of fat grafting, among others [71, 79–82, 95, 96]. The acting mechanisms in this scenario have been attributed, in part, to an increase in the aerobic metabolism and angiogenesis processes, leading to an improvement of the natural vascularization phenomena . Moreover, several investigations have shown the beneficial effects of HBOT on wound healing [91–93], relieving migraine headaches , and local tumour control, mortality, and recurrence for cancers of the head, neck, and uterine cervix [89, 90].
Regarding metabolic alterations, there is evidence that HBOT and NBOT are able to attenuate systemic inflammation. On a zymosan-induced generalized inflammation mouse model, 80% survival rate of mice treated with 100% O2 with respect to control has been reported . Moreover, zymosan mice treated with 100% O2 showed significant reductions in the expression of inflammatory cytokines and little distortion in overall tissue architecture compared to the animals maintained in room air. Finally, O2 treated mice also presented significant improvements in serum alanine aminotransferase (ALT) test, aspartate aminotransferase (AST) test, and creatinine. Importantly, amelioration of inflammation and pain was also obtained in carrageenan-induced rats exposed to HBOT . Taken together, these researches clearly illustrate that 100% O2 treatment may improve organ structure and function as well as suppress the inflammatory cascade response, suggesting the possibility of oxygen treatment to be used in chronic cases of inflammation.
Furthermore, there is evidence that HBOT reduces blood glucose levels in patients with type 2 diabetes and hypertension . This beneficial outcome may be due to an increase in glucose utilization by the brain, a feature that has been documented after HBOT exposure in rats , while insulin has also been described to have important actions in these circumstances. Indeed, a recent study has shown that HBOT (100% O2; 2.0 ATA for 2 h) was able to increase insulin sensitivity in both healthy subjects and obese individuals with type 2 diabetes. Of note, this positive effect, which authors state to be equivalent to that found after moderate weight loss, was observed within 3 days of HBOT and maintained for 30 sessions . However, the implicated mechanisms are unknown and require further elucidation.
Interestingly, various studies have provided evidence for an analogous beneficial effect under hypoxic conditions, on glucose homeostasis and adipose tissue inflammation, in rodents [98, 99], and on insulin sensitivity in diabetic patients  and obese subjects . Furthermore, several studies have also reported healthier values of blood pressure for humans that have exercised under hypoxia [102–104]. Nevertheless, other researchers have found no significant differences in obese people in blood glucose levels  and in obese people suffering sleep apnea-hypopnea syndrome in the blood levels of glucose, insulin, and relevant inflammatory parameters .
In addition, Obstructive Sleep Apnea (OSA), which appears to be a direct cause and a direct consequence of weight gain , is benefitted by the use of hyperoxia primarily based on its ability to reduce loop gain (LG), defined as the ratio of the ventilatory overshoot to the preceding reduction in ventilation .
Overall, these studies evidence that oxygen exposure has also important positive effects at a systemic level, being able to ameliorate inflammation and metabolic disruptions, which are features commonly presented in obesity. Considering that oxygen treatment may also be harmful due to proinflammatory outcomes, next steps should focus on investigating the delicate balance between oxygen protection and toxicity, determining the optimal duration, partial pressure, and timing of treatment, among others. In this sense, it is interesting to note that weight reduction increases partial oxygen arterial blood pressure (PaO2) and, also, that morbidly obese women seem to have at rest a better gas exchange .
5. Studies Related to Hyperoxia and Its Associated Molecular Effects
Several studies have reported that high oxygen concentrations can modulate mRNA expression of several genes and related protein secretion (some genes of interest for the topic of this review are listed in Table 1). For example, clinical and experimental studies have demonstrated that increasing oxygen concentrations in hypoxic and/or ischemic wounds accelerate the healing process by increasing blood vessels growth . Specifically, this study observed an increase of VEGF synthesis in wounds of Sprague-Dawley rats exposed to HBOT (100% O2 for 90 minutes twice daily for 7 days). Moreover, after 5 h of HBOT (90 min at 97.5% O2 at 2.4 ATA) nineteen genes involved in adhesion, angiogenesis, inflammation, and oxidative stress were downregulated . Notably, only angiogenin gene expression (which promotes both angiogenesis and nitric oxide production) was upregulated. This situation induced a decrease in endothelial Il-8 mRNA expression and further protein secretion, leading to an alleviation of inflammatory processes during chronic wound healing. Indeed, a study performed in mice found out that the cholinergic pathway seems to be the underlying mechanism by which the HBOT has an anti-inflammatory role . On the other hand, neonatal rats exposed to NBOT had long term adverse effects related to cardiovascular and renal dysfunctions in the adulthood .
|Angptl4: Angiopoietin-like 4; Hif-1α: hypoxia-inducible factor-1α; Il-1: Interleukin-1; Il-6: Interleukin-6; Il-8: Interleukin-8; Tnf-α: tumor necrosis factor-α; Vegf: vascular endothelial growth factor; ROS: reactive oxygen species; BAL: bronchoalveolar lavage; CIH: chronic intermittent hypoxia; ILD: interstitial lung disease; UVEC: umbilical vein endothelial cells; ND: no data; ns: no significant difference detected.|
Regarding lung injury, a study carried out in alveolar macrophages obtained from children with interstitial lung disease observed a decrease in TNF-α, IL-1, and IL-6 expression and an increase in Interleukin-8 (IL-8) expression after hyperoxia exposure . These data confirmed that hyperoxia induces changes in mRNA and protein levels in macrophages. The effect of HBOT and NBOT was analysed in Sprague-Dawley rat newborns exposed to 8% O2 for 2 h. One hour after hypoxia exposure mice were treated with 100% O2 under normobaric or hyperbaric conditions. Results confirmed that a single administration of HBOT or NBOT dose dependently reduced the hypoxic-ischemic-induced elevation of HIF-1α . Indeed, oxygen regulates the degradation of HIF-1α, and the HIF-1α-depending gene regulation is responsible for several different genetic expressions such as erythropoietin (EPO) and VEGF. These genes are frequently expressed in parallel, leading to the possibility that HIF induction could stimulate immune response by inflammatory cells . For example, after hyperoxia treatment, VEGF downregulation could decrease tumour angiogenesis, and the induction of EPO-expression could provide cytoprotection, processes that could be deleterious for cancer cells while helping nonmalignant cells (at least neural and cardiac) to be protected from the side effects of chemotherapy . Nonetheless the influence of HBOT on HIF isoforms expression in other cell types or tissues is variable . In this regard, no changes were observed in Hif-1α gene expression modifications in 3T3-L1 adipocytes exposed to 95% O2 . Thereby further experiments need to be performed, always bearing in mind that HIF-1α mRNA expression is particularly unstable. Therefore, data related to HIF-1α mRNA expression should be interpreted with prudence.
Concerning O2 treatment and adipose tissue, our group was the first to evaluate the effect of hyperoxia (95% O2; 24 or 48 h) on 3T3-L1 adipocytes. In these experiments, a strong proinflammatory response was observed, as demonstrated by the release of intra- and extracellular ROS and the upregulation of proinflammatory adipokines such as Il-6 and Mcp-1 [46, 69]. A strong correlation between Mcp-1 mRNA expression and ROS release was also found , a result that is in accordance with other studies showing that ROS production could increase Mcp-1 expression . However, other interesting outcomes were observed, such as upregulation of peroxisome proliferator-activated receptor gamma (Ppar-γ) signalling . This finding is in agreement with the above-mentioned studies linking O2 therapy and amelioration of insulin sensitivity and suggests that adipose tissue may also contribute to this feature. Finally, hyperoxia caused a decrease in the expression of Angiopoietin-like 4 (Angptl4) [46, 69], which is a protein that regulates plasma triacylglycerides metabolism by inhibiting lipoprotein lipase . In this context, some authors have proposed that elevated ANGPTL4 expression might be involved in hypertriglyceridemia in patients with insulin resistance  and other hypoxic conditions . Thus, a downregulation in Angptl4 expression, as it occurs with hyperoxia in 3T3-L1 adipocytes, might contribute to ameliorating these metabolic disorders. Furthermore, glycerol and lactate release were increased and decreased, respectively, under an elevated oxygen exposure in 3T3-L1 adipocytes [46, 69], and in male Wistar rats fed with control diet a similar effect on lactate was found (Pablo Quintero, Pedro González-Muniesa, and J. Alfredo Martinez, unpublished results). Lactate inhibits lipolysis in adipose tissue by mediating, through GPR81, the antilipolytic action of insulin , and therefore a reduction in lactate might be considered beneficial against the appearance and development of complications associated with obesity. From these experiments, it can be gathered that hyperoxia activates a pernicious proinflammatory status although it seems to have beneficial effects on glucose and lipid metabolism [46, 69]. In contrast with this, a study by Hodson et al. 2013 has reported in humans an inverse relationship between the amount of lactate released by adipose tissue and the BMI of the subject . Interestingly, hyperoxia in mice leads to weight loss and an increase in leptin, an adipokine involved in the regulation of food intake, although it seems that this weight loss is not dependent on leptin . Intriguingly, a similar result was found in mice after 21 days being exposed to chronic hypoxia (8% O2), in which these animals lose weight and adipose tissue mass and size, and leptin concentrations were decreased . Nevertheless, more studies are needed to obtain a better understanding of these mechanisms and, more importantly, to determine the optimum duration and timing of treatment to avoid undesired effects. Moreover, some results are contradictory or not comparable due to the wide variety of concentrations and/or duration of the exposures and also the experimental models and analyzed tissues. For instance, the gene expression of the proinflammatory cytokine IL-8 was increased in alveolar macrophages from interstitial lung disease treated with 95% O2 for 48 h , while decreased in chronic wound of umbilical vein endothelial cells treated with 95% O2 for 90 minutes . These data suggest that more research is needed regarding the different tissues, experimental models, and type of treatments to elucidate the benefits and disadvantages of hyperoxia therapy.
6. Conclusions and Future Directions
Oxygen homeostasis is of fundamental importance to the cell and to maintain equilibrium within the existing complex relationships between oxygen concentration, energy metabolism, acid-base status, redox state, and the control of cell growth and proliferation . The studies herein reviewed evidenced that an abnormal level of oxygen partial pressure in expanded adipose tissue may be a triggering factor for the release of inflammatory mediators. Moreover, several studies have demonstrated that treatment with hyperoxia/hypoxia may play an important role in the regulation of inflammatory responses and metabolic disorders, such as insulin resistance. Furthermore, aerobic exercise, which increases body general oxygenation, seems to play a main role in visceral adipose tissue reduction .
Taking into account the information presented in this review and further preliminary experimental data, we put forward some questions in order to address future investigations about metaflammation treatment with hyperoxia exposure:(1)Which is the origin of proinflammatory signalling in obesity and its role in obesity-associated manifestations?(2)Would HIF-1α signalling be a possible therapeutic target in an obesity context?(3)Which are the possible effects of oxygen therapy as an obesity treatment, particularly on metaflammation?
Yet, more studies are needed to shed more light on the molecular effects of oxygen (hyperoxia or hypoxia) and the concentration available of this gas in various fat depots from humans with different phenotypes, for example, those suffering obesity with or without insulin resistance. Maybe one day this therapy could be used as an advantageous tool to improve various diseases concerning inflammatory conditions.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
Pedro González-Muniesa and J. Alfredo Martinez are researchers of CIBERobn Physiopathology of Obesity, IDISNA, Navarra’s Health Research Institute, and Nutrition Network and Línea Especial, Nutrición y Obesidad (University of Navarra); Amaya Lopez-Pascual fully acknowledges the fellowships to Asociación de Amigos de la Universidad de Navarra (ADA) and the FPU from the Spanish Ministry of Education, Culture and Sport (MECD).
- M. F. Gregor and G. S. Hotamisligil, “Inflammatory mechanisms in obesity,” Annual Review of Immunology, vol. 29, pp. 415–445, 2011.
- C. N. Lumeng and A. R. Saltiel, “Inflammatory links between obesity and metabolic disease,” The Journal of Clinical Investigation, vol. 121, no. 6, pp. 2111–2117, 2011.
- Q. He, Z. Gao, J. Yin, J. Zhang, Z. Yun, and J. Ye, “Regulation of HIF-1α activity in adipose tissue by obesity-associated factors: adipogenesis, insulin, and hypoxia,” American Journal of Physiology—Endocrinology and Metabolism, vol. 300, no. 5, pp. E877–E885, 2011.
- R. Samper-Ternent and S. Al Snih, “Obesity in older adults: epidemiology and implications for disability and disease,” Reviews in Clinical Gerontology, vol. 22, no. 1, pp. 10–34, 2012.
- K. M. Flegal, M. D. Carroll, C. L. Ogden, and L. R. Curtin, “Prevalence and trends in obesity among US adults, 1999–2008,” Journal of the American Medical Association, vol. 303, no. 3, pp. 235–241, 2010.
- P. Hossain, B. Kawar, and M. El Nahas, “Obesity and diabetes in the developing world—a growing challenge,” The New England Journal of Medicine, vol. 356, no. 3, pp. 213–215, 2007.
- G. A. Stevens, G. M. Singh, Y. Lu et al., “National, regional, and global trends in adult overweight and obesity prevalences,” Population Health Metrics, vol. 10, no. 1, article 22, 2012.
- M. Ng, T. Fleming, M. Robinson, and et al, “Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013,” The Lancet, vol. 384, no. 9945, pp. 746–781, 2014.
- F. I. Milagro, M. L. Mansego, C. De Miguel, and J. A. Martínez, “Dietary factors, epigenetic modifications and obesity outcomes: progresses and perspectives,” Molecular Aspects of Medicine, vol. 34, no. 4, pp. 782–812, 2013.
- B. L. Heitmann, K. R. Westerterp, R. J. F. Loos et al., “Obesity: lessons from evolution and the environment,” Obesity Reviews, vol. 13, no. 10, pp. 910–922, 2012.
- E. J. McAllister, N. V. Dhurandhar, S. W. Keith et al., “Ten putative contributors to the obesity epidemic,” Critical Reviews in Food Science and Nutrition, vol. 49, no. 10, pp. 868–913, 2009.
- P. Trayhurn, “Hypoxia and adipocyte physiology: implications for adipose tissue dysfunction in obesity,” Annual Review of Nutrition, vol. 34, pp. 207–236, 2014.
- P. Trayhurn and I. S. Wood, “Adipokines: inflammation and the pleiotropic role of white adipose tissue,” British Journal of Nutrition, vol. 92, no. 3, pp. 347–355, 2004.
- G. H. Goossens and E. E. Blaak, “Adipose tissue dysfunction and impaired metabolic health in human obesity: a matter of oxygen?” Frontiers in Endocrinology, vol. 6, article 55, 2015.
- G. H. Goossens, A. Bizzarri, N. Venteclef et al., “Increased adipose tissue oxygen tension in obese compared with lean men is accompanied by insulin resistance, impaired adipose tissue capillarization, and inflammation,” Circulation, vol. 124, no. 1, pp. 67–76, 2011.
- L. Hodson, S. M. Humphreys, F. Karpe, and K. N. Frayn, “Metabolic signatures of human adipose tissue hypoxia in obesity,” Diabetes, vol. 62, no. 5, pp. 1417–1425, 2013.
- F. J. Lippl, S. Neubauer, S. Schipfer et al., “Hypobaric hypoxia causes body weight reduction in obese subjects,” Obesity, vol. 18, no. 4, pp. 675–681, 2010.
- K. R. Westerterp, “Energy and water balance at high altitude,” News in Physiological Sciences, vol. 16, no. 3, pp. 134–137, 2001.
- H.-C. Gunga, D. Fries, E. Humpeler et al., “Austrian Moderate Altitude Study (AMAS 2000)—fluid shifts, erythropoiesis, and angiogenesis in patients with metabolic syndrome at moderate altitude (≅1700 m),” European Journal of Applied Physiology, vol. 88, no. 6, pp. 497–505, 2003.
- A. M. W. J. Schols and K. R. Westerterp, “Hypoxia, nitrogen balance and body weight,” The European Respiratory Journal, vol. 20, no. 2, pp. 252–253, 2002.
- P. González-Muniesa, P. Quintero, J. De Andrés, and J. A. Martínez, “Hypoxia: a consequence of obesity and also a tool to treat excessive weight loss,” Sleep & Breathing, vol. 19, no. 1, pp. 7–8, 2015.
- P. Trayhurn, “Hypoxia and adipose tissue function and dysfunction in obesity,” Physiological Reviews, vol. 93, no. 1, pp. 1–21, 2013.
- R. Medzhitov, “Origin and physiological roles of inflammation,” Nature, vol. 454, no. 7203, pp. 428–435, 2008.
- J. A. Martinez, P. Cordero, J. Campion, and F. I. Milagro, “Interplay of early-life nutritional programming on obesity, inflammation and epigenetic outcomes,” Proceedings of the Nutrition Society, vol. 71, no. 2, pp. 276–283, 2012.
- S. Nayadu, G. Kaur, G. Gudi, and V. Addepalli, “The potentials of selected therapeutic targets for inflammation: a snapshot,” Recent Patents on Inflammation and Allergy Drug Discovery, vol. 6, no. 2, pp. 137–146, 2012.
- K. S. vel Szic, M. N. Ndlovu, G. Haegeman, and W. V. Berghe, “Nature or nurture: let food be your epigenetic medicine in chronic inflammatory disorders,” Biochemical Pharmacology, vol. 80, no. 12, pp. 1816–1832, 2010.
- A. González-Chávez, S. Elizondo-Argueta, G. Gutiérrez-Reyes, and J. I. León-Pedroza, “Pathophysiological implications between chronic inflammation and the development of diabetes and obesity,” Cirugia y Cirujanos, vol. 79, no. 2, pp. 209–216, 2011.
- S. Sun, Y. Ji, S. Kersten, and L. Qi, “Mechanisms of inflammatory responses in obese adipose tissue,” Annual Review of Nutrition, vol. 32, pp. 261–286, 2012.
- P. Trayhurn, B. Wang, and I. S. Wood, “Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity?” British Journal of Nutrition, vol. 100, no. 2, pp. 227–235, 2008.
- K. Fjeldborg, S. B. Pedersen, H. J. Møller, T. Christiansen, M. Bennetzen, and B. Richelsen, “Human adipose tissue macrophages are enhanced but changed to an anti-inflammatory profile in obesity,” Journal of Immunology Research, vol. 2014, Article ID 309548, 10 pages, 2014.
- M. G. Farb, S. Bigornia, M. Mott et al., “Reduced adipose tissue inflammation represents an intermediate cardiometabolic phenotype in obesity,” Journal of the American College of Cardiology, vol. 58, no. 3, pp. 232–237, 2011.
- S. Thalmann and C. A. Meier, “Local adipose tissue depots as cardiovascular risk factors,” Cardiovascular Research, vol. 75, no. 4, pp. 690–701, 2007.
- S. P. Weisberg, D. McCann, M. Desai, M. Rosenbaum, R. L. Leibel, and A. W. Ferrante Jr., “Obesity is associated with macrophage accumulation in adipose tissue,” The Journal of Clinical Investigation, vol. 112, no. 12, pp. 1796–1808, 2003.
- J. A. Bell, M. Kivimaki, and M. Hamer, “Metabolically healthy obesity and risk of incident type 2 diabetes: a meta-analysis of prospective cohort studies,” Obesity Reviews, vol. 15, no. 6, pp. 504–515, 2014.
- E. Navarro, A. N. Funtikova, M. Fíto, and H. Schröder, “Can metabolically healthy obesity be explained by diet, genetics, and inflammation?” Molecular Nutrition & Food Research, vol. 59, no. 1, pp. 75–93, 2015.
- J. Z. Ilich, O. J. Kelly, Y. Kim, and M. T. Spicer, “Low-grade chronic inflammation perpetuated by modern diet as a promoter of obesity and osteoporosis,” Archives of Industrial Hygiene and Toxicology, vol. 65, no. 2, pp. 139–148, 2014.
- G. Marrazzo, I. Barbagallo, F. Galvano et al., “Role of dietary and endogenous antioxidants in diabetes,” Critical Reviews in Food Science and Nutrition, vol. 54, no. 12, pp. 1599–1616, 2014.
- V. D'Souza, P. Chavan-Gautam, and S. Joshi, “Counteracting oxidative stress in pregnancy through modulation of maternal micronutrients and omega-3 fatty acids,” Current Medicinal Chemistry, vol. 20, no. 37, pp. 4777–4783, 2013.
- S. Le Lay, G. Simard, M. C. Martinez, and R. Andriantsitohaina, “Oxidative stress and metabolic pathologies: from an adipocentric point of view,” Oxidative Medicine and Cellular Longevity, vol. 2014, Article ID 908539, 18 pages, 2014.
- U. Özcan, Q. Cao, E. Yilmaz et al., “Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes,” Science, vol. 306, no. 5695, pp. 457–461, 2004.
- I. S. Wood, F. P. de Heredia, B. Wang, and P. Trayhurn, “Cellular hypoxia and adipose tissue dysfunction in obesity,” The Proceedings of the Nutrition Society, vol. 68, no. 4, pp. 370–377, 2009.
- I. Bondia-Pons, L. Ryan, and J. A. Martinez, “Oxidative stress and inflammation interactions in human obesity,” Journal of Physiology and Biochemistry, vol. 68, no. 4, pp. 701–711, 2012.
- K. Lolmède, C. Duffaut, A. Zakaroff-Girard, and A. Bouloumié, “Immune cells in adipose tissue: key players in metabolic disorders,” Diabetes & Metabolism, vol. 37, no. 4, pp. 283–290, 2011.
- R. W. O'Rourke, A. E. White, M. D. Metcalf et al., “Hypoxia-induced inflammatory cytokine secretion in human adipose tissue stromovascular cells,” Diabetologia, vol. 54, no. 6, pp. 1480–1490, 2011.
- T. Cramer and R. S. Johnson, “A novel role for the hypoxia inducible transcription factor HIF-1alpha: critical regulation of inflammatory cell function,” Cell Cycle, vol. 2, no. 3, pp. 192–193, 2003.
- P. Quintero, P. González-Muniesa, D. F. García-Díaz, and J. A. Martínez, “Effects of hyperoxia exposure on metabolic markers and gene expression in 3T3-L1 adipocytes,” Journal of Physiology and Biochemistry, vol. 68, no. 4, pp. 663–669, 2012.
- S. Rocha, “Gene regulation under low oxygen: holding your breath for transcription,” Trends in Biochemical Sciences, vol. 32, no. 8, pp. 389–397, 2007.
- J. Ye, Z. Gao, J. Yin, and Q. He, “Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice,” The American Journal of Physiology—Endocrinology and Metabolism, vol. 293, no. 4, pp. E1118–E1128, 2007.
- B. Wang, I. S. Wood, and P. Trayhurn, “Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes,” Pflügers Archiv—European Journal of Physiology, vol. 455, no. 3, pp. 479–492, 2007.
- S. Famulla, A. Horrighs, A. Cramer, H. Sell, and J. Eckel, “Hypoxia reduces the response of human adipocytes towards TNFα resulting in reduced NF-κB signaling and MCP-1 secretion,” International Journal of Obesity, vol. 36, no. 7, pp. 986–992, 2012.
- N. Ferrara, H.-P. Gerber, and J. LeCouter, “The biology of VEGF and its receptors,” Nature Medicine, vol. 9, no. 6, pp. 669–676, 2003.
- B. Blouw, H. Song, T. Tihan et al., “The hypoxic response of tumors is dependent on their microenvironment,” Cancer Cell, vol. 4, no. 2, pp. 133–146, 2003.
- B. Chen, K. S. L. Lam, Y. Wang et al., “Hypoxia dysregulates the production of adiponectin and plasminogen activator inhibitor-1 independent of reactive oxygen species in adipocytes,” Biochemical and Biophysical Research Communications, vol. 341, no. 2, pp. 549–556, 2006.
- S. Famulla, R. Schlich, H. Sell, and J. Eckel, “Differentiation of human adipocytes at physiological oxygen levels results in increased adiponectin secretion and isoproterenol-stimulated lipolysis,” Adipocyte, vol. 1, no. 3, pp. 132–181, 2014.
- I. Mack, R. S. BelAiba, T. Djordjevic, A. Görlach, H. Hauner, and B. L. Bader, “Functional analyses reveal the greater potency of preadipocytes compared with adipocytes as endothelial cell activator under normoxia, hypoxia, and TNFalpha exposure,” The American Journal of Physiology—Endocrinology and Metabolism, vol. 297, no. 3, pp. E735–E748, 2009.
- B. Wang, I. S. Wood, and P. Trayhurn, “PCR arrays identify metallothionein-3 as a highly hypoxia-inducible gene in human adipocytes,” Biochemical and Biophysical Research Communications, vol. 368, no. 1, pp. 88–93, 2008.
- Q. Yao, M.-K. Shin, J. C. Jun et al., “Effect of chronic intermittent hypoxia on triglyceride uptake in different tissues,” Journal of Lipid Research, vol. 54, no. 4, pp. 1058–1065, 2013.
- K. Geiger, A. Leiherer, A. Muendlein et al., “Identification of hypoxia-induced genes in human SGBS adipocytes by microarray analysis,” PLoS ONE, vol. 6, no. 10, Article ID e26465, 2011.
- D. Mazzatti, F.-L. Lim, A. O'Hara, I. S. Wood, and P. Trayhurn, “A microarray analysis of the hypoxia-induced modulation of gene expression in human adipocytes,” Archives of Physiology and Biochemistry, vol. 118, no. 3, pp. 112–120, 2012.
- K. M. Oliver, J. F. Garvey, C. T. Ng et al., “Hypoxia activates NF-κB-dependent gene expression through the canonical signaling pathway,” Antioxidants and Redox Signaling, vol. 11, no. 9, pp. 2057–2064, 2009.
- G. L. Semenza, “Hypoxia-inducible factor 1: master regulator of O2 homeostasis,” Current Opinion in Genetics and Development, vol. 8, no. 5, pp. 588–594, 1998.
- M. C. Brahimi-Horn and J. Pouysségur, “Oxygen, a source of life and stress,” FEBS Letters, vol. 581, no. 19, pp. 3582–3591, 2007.
- G. L. Semenza, “HIF-1 and mechanisms of hypoxia sensing,” Current Opinion in Cell Biology, vol. 13, no. 2, pp. 167–171, 2001.
- S. Kushal, B. B. Lao, L. K. Henchey et al., “Protein domain mimetics as in vivo modulators of hypoxia-inducible factor signaling,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 39, pp. 15602–15607, 2013.
- M. Lawton, M. Tong, F. Gundogan, J. R. Wands, and S. M. De La Monte, “Aspartyl-(asparaginyl) beta-hydroxylase, hypoxia-inducible factor-alpha and Notch cross-talk in regulating neuronal motility,” Oxidative Medicine and Cellular Longevity, vol. 3, no. 5, pp. 347–356, 2010.
- Z. E. Floyd, G. Kilroy, X. Wu, and J. M. Gimble, “Effects of prolyl hydroxylase inhibitors on adipogenesis and hypoxia inducible factor 1 alpha levels under normoxic conditions,” Journal of Cellular Biochemistry, vol. 101, no. 6, pp. 1545–1557, 2007.
- X. M. Leverve, “To cope with oxygen: a long and still tumultuous story for life,” Critical Care Medicine, vol. 36, no. 2, pp. 637–638, 2008.
- P. Quintero, F. I. Milagro, J. Campión, and J. A. Martínez, “Impact of oxygen availability on body weight management,” Medical Hypotheses, vol. 74, no. 5, pp. 901–907, 2010.
- P. Quintero, P. González-Muniesa, and J. A. Martínez, “Influence of different oxygen supply on metabolic markers and gene response in murine adipocytes,” Journal of Biological Regulators and Homeostatic Agents, vol. 26, no. 3, pp. 379–388, 2012.
- A.-S. A. Haffor and O. S. Alttas, “Effects of exposure of rats to periodic versus continuous hyperoxia on antioxidant potentials and free radical production in relation to ultrastructural changes in myocardial cells,” Inhalation Toxicology, vol. 22, no. 10, pp. 797–804, 2010.
- M. S. Arkovitz, C. Szabó, V. F. Garcia, H. R. Wong, and J. R. Wispé, “Differential effects of hyperoxia on the inducible and constitutive isoforms of nitric oxide synthase in the lung,” Shock, vol. 7, no. 5, pp. 345–350, 1997.
- W. P. Daugherty, J. E. Levasseur, D. Sun, G. L. Rockswold, and M. R. Bullock, “Effects of hyperbaric oxygen therapy on cerebral oxygenation and mitochondrial function following moderate lateral fluid-percussion injury in rats,” Journal of Neurosurgery, vol. 101, no. 3, pp. 499–504, 2004.
- S. J. Hughes, W. Yang, M. Juszczak et al., “Effect of inspired oxygen on portal and hepatic oxygenation: effective arterialization of portal blood by hyperoxia,” Cell Transplantation, vol. 13, no. 7-8, pp. 801–808, 2004.
- S. R. Thom, “Hyperbaric oxygen: its mechanisms and efficacy,” Plastic and Reconstructive Surgery, vol. 127, no. 1, pp. 131S–141S, 2011.
- P. Desmarquest, K. Chadelat, S. Corroyer, V. Cazals, and A. Clement, “Effect of hyperoxia on human macrophage cytokine response,” Respiratory Medicine, vol. 92, no. 7, pp. 951–960, 1998.
- N. S. Al-Waili, G. J. Butler, J. Beale et al., “Influences of hyperbaric oxygen on blood pressure, heart rate and blood glucose levels in patients with diabetes mellitus and hypertension,” Archives of Medical Research, vol. 37, no. 8, pp. 991–997, 2006.
- D. De Bels, F. Corazza, P. Germonpré, and C. Balestra, “The normobaric oxygen paradox: a novel way to administer oxygen as an adjuvant treatment for cancer?” Medical Hypotheses, vol. 76, no. 4, pp. 467–470, 2011.
- H. D. Wilson, J. R. Wilson, and P. N. Fuchs, “Hyperbaric oxygen treatment decreases inflammation and mechanical hypersensitivity in an animal model of inflammatory pain,” Brain Research, vol. 1098, no. 1, pp. 126–128, 2006.
- E. H. H. Chiu, C.-S. Liu, T.-Y. Tan, and K.-C. Chang, “Venturi mask adjuvant oxygen therapy in severe acute ischemic stroke,” Archives of Neurology, vol. 63, no. 5, pp. 741–744, 2006.
- A. B. Singhal, T. Banner, L. Roccatagliata et al., “A pilot study of normobaric oxygen therapy in acute ischemic stroke,” Stroke, vol. 36, no. 4, pp. 797–802, 2005.
- L. Sun, H. Strelow, G. Mies, and R. Veltkamp, “Oxygen therapy improves energy metabolism in focal cerebral ischemia,” Brain Research, vol. 1415, pp. 103–108, 2011.
- H. Kato, J. Araki, K. Doi et al., “Normobaric hyperoxygenation enhances initial survival, regeneration, and final retention in fat grafting,” Plastic and Reconstructive Surgery, vol. 134, no. 5, pp. 951–959, 2014.
- F. L. Contreras, M. Kadekaro, and H. M. Eisenberg, “The effect of hyperbaric oxygen on glucose utilization in a freeze-traumatized rat brain,” Journal of Neurosurgery, vol. 68, no. 1, pp. 137–141, 1988.
- V. Roth, M. S. Herron, R. A. Bueno Jr., C. B. Chambers, and M. W. Neumeister, “Stimulating angiogenesis by Hyperbaric oxygen in an isolated tissue construct,” Undersea & Hyperbaric Medicine, vol. 38, no. 6, pp. 509–514, 2011.
- D. Wilkinson, I. M. Chapman, and L. K. Heilbronn, “Hyperbaric oxygen therapy improves peripheral insulin sensitivity in humans,” Diabetic Medicine, vol. 29, no. 8, pp. 986–989, 2012.
- J. W. Calvert, J. Cahill, M. Yamaguchi-Okada, and J. H. Zhang, “Oxygen treatment after experimental hypoxia-ischemia in neonatal rats alters the expression of HIF-1α and its downstream target genes,” Journal of Applied Physiology, vol. 101, no. 3, pp. 853–865, 2006.
- A. B. Singhal, E. Ratai, T. Benner et al., “Magnetic resonance spectroscopy study of oxygen therapy in ischemic stroke,” Stroke, vol. 38, no. 10, pp. 2851–2854, 2007.
- L. Huang and A. Obenaus, “Hyperbaric oxygen therapy for traumatic brain injury,” Medical Gas Research, vol. 1, no. 1, p. 21, 2011.
- M. H. Bennett, C. French, A. Schnabel, J. Wasiak, and P. Kranke, “Normobaric and hyperbaric oxygen therapy for migraine and cluster headache,” Cochrane Database of Systematic Reviews, no. 3, Article ID CD005219, 2008.
- M. H. Bennett, J. Feldmeier, N. Hampson, R. Smee, and C. Milross, “Hyperbaric oxygen therapy for late radiation tissue injury,” Cochrane Database of Systematic Reviews, vol. 3, Article ID CD005005, 2012.
- S. Kaur, M. Pawar, N. Banerjee, and R. Garg, “Evaluation of the efficacy of hyperbaric oxygen therapy in the management of chronic nonhealing ulcer and role of periwound transcutaneous oximetry as a predictor of wound healing response: a randomized prospective controlled trial,” Journal of Anaesthesiology Clinical Pharmacology, vol. 28, no. 1, pp. 70–75, 2012.
- L. Ma, P. Li, Z. Shi, T. Hou, X. Chen, and J. Du, “A prospective, randomized, controlled study of hyperbaric oxygen therapy: effects on healing and oxidative stress of ulcer tissue in patients with a diabetic foot ulcer,” Ostomy/Wound Management, vol. 59, no. 3, pp. 18–24, 2013.
- Z. Peng, S. Wang, X. Huang, and P. Xiao, “Effect of hyperbaric oxygen therapy on patients with herpes zoster,” Undersea and Hyperbaric Medicine, vol. 39, no. 6, pp. 1083–1087, 2012.
- A. Y. Sheikh, J. J. Gibson, M. D. Rollins, H. W. Hopf, Z. Hussain, and T. K. Hunt, “Effect of hyperoxia on vascular endothelial growth factor levels in a wound model,” Archives of Surgery, vol. 135, no. 11, pp. 1293–1297, 2000.
- M. L. Edwards, “Hyperbaric oxygen therapy. Part 2: application in disease,” Journal of Veterinary Emergency and Critical Care, vol. 20, no. 3, pp. 289–297, 2010.
- A. B. Singhal, “A review of oxygen therapy in ischemic stroke,” Neurological Research, vol. 29, no. 2, pp. 173–183, 2007.
- Z. Zhang, X. Bai, K. Du et al., “Activation of cholinergic anti-inflammatory pathway contributes to the protective effects of 100% oxygen inhalation on zymosan-induced generalized inflammation in mice,” The Journal of Surgical Research, vol. 174, no. 2, pp. e75–e83, 2012.
- L.-L. Chiu, S.-W. Chou, Y.-M. Cho et al., “Effect of prolonged intermittent hypoxia and exercise training on glucose tolerance and muscle GLUT4 protein expression in rats,” Journal of Biomedical Science, vol. 11, no. 6, pp. 838–846, 2004.
- B. van den Borst, A. M. W. J. Schols, C. de Theije et al., “Characterization of the inflammatory and metabolic profile of adipose tissue in a mouse model of chronic hypoxia,” Journal of Applied Physiology, vol. 114, no. 11, pp. 1619–1628, 2013.
- R. Mackenzie, N. Maxwell, P. Castle, G. Brickley, and P. Watt, “Acute hypoxia and exercise improve insulin sensitivity (S(I) (2*)) in individuals with type 2 diabetes,” Diabetes/Metabolism Research and Reviews, vol. 27, no. 1, pp. 94–101, 2011.
- V. Lecoultre, C. M. Peterson, J. D. Covington et al., “Ten nights of moderate hypoxia improves insulin sensitivity in obese humans,” Diabetes Care, vol. 36, no. 12, pp. e197–e198, 2013.
- Z. Kong, Y. Zang, and Y. Hu, “Normobaric hypoxia training causes more weight loss than normoxia training after a 4-week residential camp for obese young adults,” Sleep & Breathing, vol. 18, no. 3, pp. 591–597, 2014.
- P. González-Muniesa, C. de Oliveira, F. Pérez de Heredia, M. P. Thompson, and P. Trayhurn, “Fatty acids and hypoxia stimulate the expression and secretion of the adipokine ANGPTL4 (angiopoietin-like protein 4/ fasting-induced adipose factor) by human adipocytes,” Journal of Nutrigenetics and Nutrigenomics, vol. 4, no. 3, pp. 146–153, 2011.
- P. González-Muniesa, A. Lopez-Pascual, J. de Andrés et al., “Impact of intermittent hypoxia and exercise on blood pressure and metabolic features from obese subjects suffering sleep apnea-hypopnea syndrome,” Journal of Physiology and Biochemistry, vol. 71, no. 3, pp. 589–599, 2015.
- H. Gatterer, S. Haacke, M. Burtscher et al., “Normobaric intermittent hypoxia over 8 months does not reduce body weight and metabolic risk factors—a randomized, single blind, placebo-controlled study in normobaric hypoxia and normobaric sham hypoxia,” Obesity Facts, vol. 8, no. 3, pp. 200–209, 2015.
- M. St-Onge and A. Shechter, “Sleep disturbances, body fat distribution, food intake and/or energy expenditure: pathophysiological aspects,” Hormone Molecular Biology and Clinical Investigation, vol. 17, no. 1, pp. 29–37, 2014.
- B. A. Edwards, S. A. Sands, R. L. Owens et al., “Effects of hyperoxia and hypoxia on the physiological traits responsible for obstructive sleep apnoea,” The Journal of Physiology, vol. 592, no. 20, pp. 4523–4535, 2014.
- G. S. Zavorsky and S. L. Hoffman, “Pulmonary gas exchange in the morbidly obese,” Obesity Reviews, vol. 9, no. 4, pp. 326–339, 2008.
- A. C. Kendall, J. L. Whatmore, L. W. Harries, P. G. Winyard, G. R. Smerdon, and P. Eggleton, “Changes in inflammatory gene expression induced by hyperbaric oxygen treatment in human endothelial cells under chronic wound conditions,” Experimental Cell Research, vol. 318, no. 3, pp. 207–216, 2012.
- H. Li, Z.-Z. Zhang, J. Zhan, X.-H. He, X.-M. Song, and Y.-L. Wang, “Protective effect of PNU-120596, a selective alpha7 nicotinic acetylcholine receptor-positive allosteric modulator, on myocardial ischemia-reperfusion injury in rats,” Journal of Cardiovascular Pharmacology, vol. 59, no. 6, pp. 507–513, 2012.
- C. Yzydorczyk, B. Comte, G. Cambonie et al., “Neonatal oxygen exposure in rats leads to cardiovascular and renal alterations in adulthood,” Hypertension, vol. 52, no. 5, pp. 889–895, 2008.
- G. F. Benderro, X. Sun, Y. Kuang, and J. C. Lamanna, “Decreased VEGF expression and microvascular density, but increased HIF-1 and 2alpha accumulation and EPO expression in chronic moderate hyperoxia in the mouse brain,” Brain Research, vol. 1471, pp. 46–55, 2012.
- Y. S. Chang, S. J. Choi, S. Y. Ahn et al., “Timing of umbilical cord blood derived mesenchymal stem cells transplantation determines therapeutic efficacy in the neonatal hyperoxic lung injury,” PLoS ONE, vol. 8, no. 1, Article ID e52419, 2013.
- J. C. Jensen, H. W. Pogrebniak, H. I. Pass et al., “Role of tumor necrosis factor in oxygen toxicity,” Journal of Applied Physiology, vol. 72, no. 5, pp. 1902–1907, 1992.
- A. Bellmeyer, J. M. Martino, N. S. Chandel, G. R. S. Budinger, D. A. Dean, and G. M. Mutlu, “Leptin resistance protects mice from hyperoxia-induced acute lung injury,” American Journal of Respiratory and Critical Care Medicine, vol. 175, no. 6, pp. 587–594, 2007.
- C. Barazzone-Argiroffo, P. Muzzin, Y. R. Donati, C.-D. Kan, M. L. Aubert, and P.-F. Piguet, “Hyperoxia increases leptin production: a mechanism mediated through endogenous elevation of corticosterone,” American Journal of Physiology: Lung Cellular and Molecular Physiology, vol. 281, no. 5, pp. L1150–L1156, 2001.
- N. Lahat, H. Bitterman, N. Yaniv, A. Kinarty, and N. Bitterman, “Exposure to hyperbaric oxygen induces tumour necrosis factor-alpha (TNF-α) secretion from rat macrophages,” Clinical & Experimental Immunology, vol. 102, no. 3, pp. 655–659, 1995.
- G. D. Marconi, S. Zara, M. De Colli et al., “Postnatal hyperoxia exposure differentially affects hepatocytes and liver haemopoietic cells in newborn rats,” PLoS ONE, vol. 9, no. 8, Article ID e105005, 2014.
- D. J. Kwak, S. D. Kwak, and E. B. Gauda, “The effect of hyperoxia on reactive oxygen species (ROS) in petrosal and nodose ganglion neurons during development (using organotypic slices),” Advances in Experimental Medicine and Biology, vol. 580, pp. 111–114, 2006.
- C. Brueckl, S. Kaestle, A. Kerem et al., “Hyperoxia-induced reactive oxygen species formation in pulmonary capillary endothelial cells in situ,” American Journal of Respiratory Cell and Molecular Biology, vol. 34, no. 4, pp. 453–463, 2006.
- Q. Zangl, A. Martignoni, S. H. Jackson et al., “Postoperative hyperoxia (60%) worsens hepatic injury in Mice,” Anesthesiology, vol. 121, no. 6, pp. 1217–1225, 2014.
- B. Adamcio, S. Sperling, N. Hagemeyer, G. Walkinshaw, and H. Ehrenreich, “Hypoxia inducible factor stabilization leads to lasting improvement of hippocampal memory in healthy mice,” Behavioural Brain Research, vol. 208, no. 1, pp. 80–84, 2010.
- S. R. Thom, “Oxidative stress is fundamental to hyperbaric oxygen therapy,” Journal of Applied Physiology, vol. 106, no. 3, pp. 988–995, 2009.
- Y. Quan, C.-T. Jiang, B. Xue, S.-G. Zhu, and X. Wang, “High glucose stimulates TNFα and MCP-1 expression in rat microglia via ROS and NF-κB pathways,” Acta Pharmacologica Sinica, vol. 32, no. 2, pp. 188–193, 2011.
- F. Mattijssen and S. Kersten, “Regulation of triglyceride metabolism by Angiopoietin-like proteins,” Biochimica et Biophysica Acta, vol. 1821, no. 5, pp. 782–789, 2012.
- T. Yamada, N. Ozaki, Y. Kato, Y. Miura, and Y. Oiso, “Insulin downregulates angiopoietin-like protein 4 mRNA in 3T3-L1 adipocytes,” Biochemical and Biophysical Research Communications, vol. 347, no. 4, pp. 1138–1144, 2006.
- K. Rooney and P. Trayhurn, “Lactate and the GPR81 receptor in metabolic regulation: implications for adipose tissue function and fatty acid utilisation by muscle during exercise,” The British Journal of Nutrition, vol. 106, no. 9, pp. 1310–1316, 2011.
- I. Ismail, S. E. Keating, M. K. Baker, and N. A. Johnson, “A systematic review and meta-analysis of the effect of aerobic vs. resistance exercise training on visceral fat,” Obesity Reviews, vol. 13, no. 1, pp. 68–91, 2012.
Copyright © 2016 Pedro González-Muniesa et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.