Marcadores de inflamación y estrés oxidativo en la prevención y reversión de la obesidad y sus comorbilidades asociadas

Résumé

Obesity and overweight are considered the biggest public health problem in the world. These disorders are characterized by an imbalance in oxidative/antioxidant status and a subclinical low-grade inflammatory state accompanied by a high risk of developing diabetes, arteriosclerotic complications, and cardiovascular disease. Metabolic syndrome (MetS) encompasses a set of cardiovascular risk factors that include obesity, insulin resistance, high triglyceride levels, low high-density lipoprotein cholesterol levels, and hypertension. The prevalence of MetS, together with that of obesity and overweight, have increased in recent years, due to the high degree of sedentary lifestyle and the intake of hypercaloric diets in the general population. Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western societies. It is characterized by the excessive accumulation of lipids, especially triglycerides, in the hepatocytes of the liver parenchyma, and consequently, it is strongly related to overweight, obesity, and insulin resistance. Oxidative stress is an important factor involved in NAFLD, MetS and obesity, which derives from an imbalance between prooxidant and antioxidant agents. The inflammatory process is a physiological response that allows the body to recover normal conditions, eliminating or inhibiting the agent causing an infection and/or cell damage, restoring the functionality of the affected tissue or organ. Margalida Monserrat Mesquida – Tesis Doctoral XXVI The general objective of this thesis is to reveal the prooxidant and proinflammatory state in patients with MetS and NAFLD and to evaluate the effects on markers of inflammation and oxidative stress of a nutritional intervention based on the MedDiet aimed at the prevention and reversal of comorbidities. associated with obesity and overweight. The results reflect that patients with MetS present a situation of higher degree of oxidative stress and a pro-inflammatory state with respect to the control group without MetS. Subjects with MetS have lower levels of antioxidant enzymes, catalase (CAT) and superoxide dismutase (SOD), and higher levels of the prooxidant enzyme myeloperoxidase (MPO) than subjects without MetS. Accordingly, plasma levels of malondialdehyde (MDA) were higher in patients with MetS, likewise, the proinflammatory state of these patients is evidenced by the presence of inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα). When comparing the population with normal weight, overweight and obesity, the results reflect differences as the Body Mass Index (BMI) of the subjects increases. Glycemia, triglyceridemia, abdominal obesity, and waist-to-height ratio (WHtR) are higher in obese patients, while these have lower HDL cholesterol levels. Overweight and obese participants present a progressive increase in circulating leukocytes and in the degree of oxidative stress, as the activities of all antioxidant enzymes in peripheral blood mononuclear cells (PBMCs), as well as the production of reactive species of oxygen (ROS), increase progressively with BMI. This increase is also reflected in proinflammatory cytokines (IL-6 and TNFα) in plasma. After 2 years of intervention in the PREDIMED-PLUS study patients, a greater reduction in abdominal obesity, blood pressure, and triglyceride levels was observed in the intervention group. Furthermore, an improvement in oxidative stress and proinflammatory markers was demonstrated with a significant reduction in the levels of MPO, xanthine oxidase (XOD), MDA, monocyte chemoattractant protein-1 (MCP1), and an increase in plasma polyphenols. Also, a decrease in ROS production in PBMCs and neutrophil levels was found after zymosan and lipopolysaccharide activation in the Abstract XXVII intervention group compared to the control group. Therefore, intervention with a hypocaloric MedDiet could be useful to improve oxidative stress and the proinflammatory state and reduce the risk of cardiovascular diseases in patients with MetS. In relation to intrahepatic fat content in patients with NAFLD after assessment by Nuclear Magnetic Resonance (MRI), participants with higher intrahepatic fat content have higher plasma levels of MDA, CAT, SOD, IL-6, cytokeratin 18 ( CK-18), irisin, but lower levels of resolvin D1, and no change in fibroblast growth factor 21 (FGF21). These markers may be useful in clinical practice. In agreement, biochemical markers (glycemia, glycosylated hemoglobin, triglycerides) progressively worsened according to intrahepatic fat content, as well as systolic and diastolic blood pressure levels. After 6 months of intervention in the lifestyle of patients with NAFLD, the main results reflect a reduction in intrahepatic fat content, which is related to an improvement in the pro/antioxidant and proinflammatory state (specifically plasma levels of CAT, irisin and CK-18) and an improvement in aerobic capacity, regardless of the type of intervention followed. In addition, greater adherence to the MedDiet is related to greater improvement in intrahepatic fat content, cardiorespiratory fitness, prooxidative stress, and proinflammatory status in patients with NAFLD after 6 months of MedDiet-based nutritional intervention. In conclusion, this doctoral thesis has shown how overweight/obese patients with MetS have a higher pro-oxidant and pro-inflammatory state compared to patients with normal weight and without MetS. Similarly, the same pattern has been observed in patients with NAFLD when compared to patients without the pathology, as well as an increase in the level of oxidative stress and proinflammatory state as the degree of steatosis increases. In addition, a nutritional intervention based on the hypocaloric Mediterranean diet pattern improves the indicators of this pro-oxidant and proinflammatory state in both MetS and NAFLD patients.