Estudio de la depleción antioxidante del eritrocito en obesidad infantil

Resumen

Obesity and overweight currently affects one third of children worldwide, and approximately 60% of cases present concomitant metabolic alterations that could trigger future complications. Among these alterations, insulin resistance has been identified as a forerunner state in the onset of characteristic metabolic disorders behind childhood obesity and its comorbidities. In this respect, it is widely recognized that both inflammation and oxidative stress play a central role in the development of these complications. However, the molecular mechanisms behind these pathogenic events remain unclear. The main aim of this Doctoral Thesis is to elucidate the molecular mechanisms involved in the inactivation of antioxidant defenses in childhood obesity and its comorbidities, in order to facilitate the search for new therapeutic targets. To this end, we recruited a sample of children and adolescents with obesity, with and without insulin resistance, as well as normal-weight healthy controls. From all these participants, plasma and erythrocyte samples were collected and subjected to complementary molecular biology and omics determinations (i.e., metallomics, metabolomics) with the aim of comprehensively characterizing the biochemical and molecular perturbations underlying the characteristic pathogenic events behind childhood obesity and metabolic syndrome. Furthermore, the study population was stratified based on different criteria, including sex, pubertal stage, and insulin secretion profile, to investigate the involvement of these potential risk/susceptibility factors in childhood obesity-related oxidative dysfunction. The application of molecular biology techniques evidenced that oxidative stress occurring in childhood obesity and metabolic syndrome may have a multifactorial origin, comprising alterations related to a decreased capacity to generate reducing power through the pentose phosphate pathway, catalase post-translational modifications, and exacerbated oxidase activity. These results were largely reflected at the metallomics level, since study subjects with obesity had decreased blood levels of essential elements involved in the antioxidant defense and metabolic control (e.g., selenium, manganese, zinc, iron) and increased levels of potentially deleterious species (e.g., copper). Finally, preliminary metabolomics results corroborate the above, showing how childhood obesity is accompanied by profound metabolic dysregulations, including failures in antioxidant systems (e.g., glutathione metabolism, generation of oxidation/nitrosylation products of nucleic acid, proteins, and lipids), various pathways related to energy metabolism (e.g., glycolysis, pentose phosphate pathway, lipid ß-oxidation, tricarboxylic acid cycle), homeostasis of amino acids (particularly branched-chain and aromatic amino acids), steroid hormones, and phospholipids, as well as other alterations related to the gut microbiota and environmental exposure factors (e.g., diet). In this vein, it should be noted that this complex set of intertwined biochemical and molecular disturbances was generally sharpened among subjects who presented concomitant insulin resistance to childhood obesity, highlighting the need of implementing personalized therapeutic tools depending on the presence/absence of metabolic complications. Furthermore, many of these disorders were found to be deeply influenced by a myriad of factors such as sex, pubertal stage, and the pattern of insulin secretion of the study subjects, thereby pinpointing the importance of addressing this interindividual variability as potential risk factors contributing to the susceptibility of developing obesity-associated complications at early ages. In summary, this Doctoral Thesis has demonstrated that childhood obesity accompanied by metabolic syndrome is characterized by profound alterations in oxidative metabolism, which in turn are affected by a wide range of individual factors (e.g., sex, pubertal stage, insulin secretion profile) and involve a number of closely interrelated molecular mechanisms.