The metabolic syndrome (MS) is a cluster of metabolic abnormalities [obesity, dyslipidemia, hypertension and hyperglycemia] predisposing to increased incidence of type 2 diabetes and cardiovascular mortality. Alarmingly, the incidence of the MS is insidiously increasing among children and adolescents, setting the stage for unprecedented levels of cardiovascular and metabolic disease in the future, with then potential for staggering morbidity and social costs. Many pathogenetic aspects of the MS are still unclear, but oxidative stress (OS), an imbalance between production of reactive oxygen species (ROS) and antioxidant defenses, is emerging as a major potential mechanism. While physical activity and nutrition are well known naturally occurring modifiers of ROS production and anti-oxidant defenses, in children key mechanisms governing the interactions among exercise, diet, and oxidative pathways, and the influence of these variables on the onset and comorbidities of the MS, have yet to be investigated. The fundamental premise of our research is that physical inactivity, high-fat diet and obesity all conspire to impair the regulation of OS in children. This general hypothesis can be tested using exercise as a quantifiable and reproducible experimental perturbation, due to its unique ability to stimulate, even in brief bouts, two main sources of ROS-- mitochondrial 02 flow and neutrophils (the latter, part of the stress/inflammatory response now known to occur with exercise in children). We propose that each of these key mechanisms (physical inactivity, high fat diet, obesity) impairs the balance between ROS generation and antioxidant defenses, rendering the child more vulnerable to the damaging effects of OS. Children will be challenged with specially designed exercise protocols, while all major variables associated with oxidative activity (oxidation of lipids, glucose, proteins, nitric oxide, DNA;neutrophil oxidative activity and gene expression, systemic antioxidants levels) will be simultaneously monitored. The following specific hypotheses will be tested: a) that even in the healthy child, a marked influence on oxidative processes during exercise is exerted by gender, maturational status and degree of physical fitness;b) that the transient hyperlipidemia caused by a high fat meal can acutely and measurably increase exercise-induced oxidative stress;and c) that pediatric obesity and metabolic syndrome are associated with exaggerated resting and exercise-induced oxidative stress. The PPG is uniquely suited for this challenging project, combining the experiences in pediatric and diabetic exercise testing of our human performance laboratory and metabolic core, with the expertise in oxidative marker analysis of three different laboratories, all collaborating in the project. Based on new and exciting preliminary studies, this research is aimed at defining these previously unexplored mechanisms, optimizing the use of exercise and diet, both diagnostically and therapeutically, to prevent or attenuate the deleterious health consequences of the metabolic syndrome in children.
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