Oxygen role in physiological and molecular markers related to metabolic disorders on in vivo and in vitro models

The presence of oxygen in our atmosphere is and has been vital for evolution and survival, not only for humans, but for the majority of living beings on Earth. In this sense, world renowned scientists have revealed that several metabolic disorders present altered oxygen partial pressure at a tissue level, while some researchers have re-considered oxygen as a nutrient. Oxygen availability could be compromised in obesity and several other metabolically related pathological manifestations such as: sleep apnea-hypopnea syndrome (SAHS), metabolic syndrome (Mets, which is a set of conditions, including: hyperglycemia, hypertension, hyperlipemia, and central adiposity), diabetes type 2 and cardiovascular disease. Strategies designed to reduce adiposity and accompanying manifestations have been mainly based on nutritional interventions and physical activity programs. However, novel therapies are needed since these approaches have not been sufficient to counteract the increasing rates of metabolic disorders. In this regard, a potential treatment is intermittent hypoxia training, which could induce several benefits from oxygen-related adaptations. Concerning prevention, other authors have reported that living at high altitude could have a protective effect against the development of abnormal metabolic conditions. On the other hand, there is a growing need for novel in vitro models to study the potential pathways involved in metabolic dysfunction in order to find appropriate therapeutic targets. Based on the existing evidence, it was theorized that the oxygen availability has a key role in obesity and related comorbidities. Thus, the general objective of the present dissertation was to investigate the implication of oxygen on metabolic disorders in vivo and in vitro. Overall, the results reported in the present dissertation evidenced the involvement of oxygen in obesity and associated metabolic disorders. Notably, individuals with obesity coupled to SAHS, showed specific cardiometabolic benefits from the treatment with intermittent hypoxia training. Moreover, our research adds novel data to the existing literature concerning the epigenetic markers and metabolic disease, as participants with lower resting oxygen consumption showed lower IL6 methylation and higher IL-6 serum levels, normally related with a pro-inflammatory status. Furthermore, the incidence and prevalence of MetS was inversely associated to altitude both in Spain and Ecuador, suggesting a physiological protective role of geographical elevation on metabolic disorders. These results confirm that oxygen availability could be one of the main features to understand, prevent and treat metabolic disorders. Furthermore, our research contributed to better comprehend not only the participation of oxygen levels in the air breathed, but also the cellular and molecular involvement of oxygen in inflammation through HIF-1α transcriptional activation, the master regulator of oxygen homeostasis. The CM in vitro model showed great similarities to the HFD mice models, commonly used in the study of obesity and related pathologies. Finally, the treatment with cerium oxide nanoparticles in metabolic syndrome-related cell lines under pro-inflammatory conditions suggested a potential insulin sensitizing effect specifically on adipose tissue and skeletal muscle as related to mitochondrial content and adiponectin expression. In conclusion, oxygen arises as a good option to further investigate not only the potential therapeutic strategies, but also new targets in the treatment and prevention of metabolic disorders.