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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
Project #
Application #
Study Section
Pediatrics Subcommittee (CHHD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Irvine
United States
Zip Code
Maharaj, Sheena; Lu, Kim D; Radom-Aizik, Shlomit et al. (2018) Inter- and intra-subject variability of nitric oxide levels in leukocyte subpopulations. Nitric Oxide 72:41-45
Radom-Aizik, Shlomit; Zaldivar, Frank P; Nance, Dwight M et al. (2018) A Translational Model of Incomplete Catch-Up Growth: Early-Life Hypoxia and the Effect of Physical Activity. Clin Transl Sci 11:412-419
Lu, Kim D; Cooper, Dan; Haddad, Fadia et al. (2017) Glucocorticoid receptor expression on circulating leukocytes in healthy and asthmatic adolescents in response to exercise. Pediatr Res 82:261-271
Lu, Kim D; Radom-Aizik, Shlomit; Haddad, Fadia et al. (2017) Glucocorticoid receptor expression on circulating leukocytes differs between healthy male and female adults. J Clin Transl Sci 1:108-114
Galant, Stanley P; Komarow, Hirsh D; Shin, Hye-Won et al. (2017) The case for impulse oscillometry in the management of asthma in children and adults. Ann Allergy Asthma Immunol 118:664-671
Lakes, Kimberley D; Guo, Yuqing; Lucas, Candice Taylor et al. (2017) Measuring Maternal Behaviors in the Neonatal Intensive Care Unit. Infants Young Child 30:124-132
Falk, B; Haddad, F; Klentrou, P et al. (2016) Differential sclerostin and parathyroid hormone response to exercise in boys and men. Osteoporos Int 27:1245-9
Radom-Aizik, Shlomit; Cooper, Dan M (2016) Bridging the Gaps: the Promise of Omics Studies in Pediatric Exercise Research. Pediatr Exerc Sci 28:194-201
Lakes, Kimberley D; Marvin, Shesha; Rowley, Jessica et al. (2016) Dancer perceptions of the cognitive, social, emotional, and physical benefits of modern styles of partnered dancing. Complement Ther Med 26:117-22
Ganesan, Goutham; Leu, Szu-Yun; Cerussi, Albert et al. (2016) Cerebral and Muscle Tissue Oxygenation During Incremental Cycling in Male Adolescents Measured by Time-Resolved Near-Infrared Spectroscopy. Pediatr Exerc Sci 28:275-85

Showing the most recent 10 out of 56 publications