It is now well recognized that inflammatory mediators and innate immune cells play essential roles in the development and progression of atherosclerosis. With the ongoing epidemic of childhood obesity (a chronic inflammatory state), precursors of atherosclerosis are becoming alarmingly apparent in the pediatric population. There is a profound gap in our understanding of: 1) mechanisms that set the stage for atherosclerosis later in life, and 2) how to prevent obesity-related vascular damage at the earliest stages. New insights suggest that physical activity ameliorates endothelial damage in part through the effect of exercise on neutrophils and monocytes, first-responding cells of innate immunity. Using a 10-week exercise-training intervention, one tailored to the capabilities of the child, we will test the following hypotheses in obese children: 1) neutrophil and monocyte genomic and epigenetic regulation and accompanying biological functions are excessively pro-inflammatory, even at rest;2) the exercise- training program will attenuate pro-inflammatory and intensify anti-inflammatory profiles of these cells;3) the exercise training reversal of deleterious effects of obesity in neutrophils and monocytes will parallel key physiological changes at the systemic, whole-organism level. Our recruitment is designed to include lower SES children who are at increased risk for obesity and its complications. To elucidate underlying cellular mechanisms, we will study how obesity-related impairments in the cellular milieu (altered carbohydrate metabolism and dyslipidemia) affect neutrophil and monocyte function. This will be accomplished by using brief bouts of exercise as an in vivo acute cell stimulus combined with in vitro cell culture studies. The investigation of neutrophils and monocytes will be accompanied by robust metrics of systemic physiological function and adaptability to training using sophisticated measures of the gas exchange response to exercise and DXA assessments of body composition. Using innovative, noninvasive tests of vascular reactivity (laser-doppler measurement of post-occlusive vasodilation), we will indirectly estimate endothelial function in a way that is feasible in children. Finally, it is increasingly recognized that episodic hypoxia [the result of sleep-disordered breathing (SDB) and obstructive sleep apnea] exacerbates inflammation, is common in obese children, and plays a major role in the many health and cognitive impairments associated with childhood obesity. Consequently, we will use state-of-the-art sleep studies to gauge SDB in our cohort and determine its interaction with the cellular and systemic response to the exercise training intervention. Despite many efforts to implement broad programs of physical activity and other lifestyle interventions, pediatric obesity remains an intractable problem. Our considerable experience in this field suggests the need for targeted approaches that: 1) identify specific disease risk mechanisms, and 2) demonstrate an impact of the proposed intervention on those mechanisms. The results of the proposed research will help channel scarce resources toward the obese children with the greatest need.

Public Health Relevance

The current epidemic of pediatric obesity remains uncontrolled, with staggering estimated healthcare cost over the next decades. Exercise is generally perceived as good for children, and, theoretically, as a key component for managing and preventing obesity. However, we still do not know what exercise dosage, mode, frequency, and duration are most effective, all factors which have substantially impeded its successful clinical use as therapy. Effective applications are also limited by our limited knowledge of the underlying mechanisms by which exercise benefits health in children. This proposal is built on emerging new understandings of the critical role played by neutrophils and monocytes in the dysregulation of this inflammatory balance in pediatric obesity, and in the pathogenesis of early endothelial damage and atherosclerosis. Beyond testing these novel hypotheses, our goal is also to shed light on both the biological basis for, and practical implementation of, exercise- training interventions in obese children, whose widespread application is sadly lacking.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Pediatrics Subcommittee (CHHD)
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University of California Irvine
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