Weight Loss Mediated Reduction in Xanthine Oxidase Activity and Uric Acid Clearance in Adolescents with Severe Obesity

By Tam, Harrison K.; Kelly, Aaron S. et al. | Childhood Obesity, August 2016 | Go to article overview

Weight Loss Mediated Reduction in Xanthine Oxidase Activity and Uric Acid Clearance in Adolescents with Severe Obesity


Tam, Harrison K., Kelly, Aaron S., Fox, Claudia K., Nathan, Brandon M., Johnson, L'Aurelle A., Childhood Obesity


[Author Affiliation]

Harrison K. Tam. 1 Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, MN.

Aaron S. Kelly. 2 Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN. 3 Department of Medicine, University of Minnesota Medical School, Minneapolis, MN.

Claudia K. Fox. 2 Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN.

Brandon M. Nathan. 2 Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN.

L'Aurelle A. Johnson. 1 Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, MN. 2 Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN.

Address correspondence to: L'Aurelle A. Johnson, PhD, MS, Department of Experimental and Clinical Pharmacology, University of Minnesota, College of Pharmacy, 308 Harvard Street SE, 7-115C WDH, Minneapolis, MN 55455, E-mail: Joh02745@umn.edu

Introduction

Obesity rates in the United States among children and adolescents ages 2-19 years old have risen nearly threefold since 1980 to a rate of nearly 17% in 2010.1 Childhood obesity is associated with increased xanthine oxidase (XO) activity and blood pressure.2-4 Specifically, elevated XO activity leads to increased production of uric acid, which has been shown to modulate blood pressure in a two-phase mechanism.5 The first phase of blood pressure modulation is uric acid dependent, whereby uric acid induces the renin-angiotensin system (RAS), which leads to acute vasoconstriction and a rise in systemic pressures. The second phase results in chronic hypertension and is uric acid independent and sodium dependent. Therefore, studying the effects of uric acid and XO before the uric acid independent second phase of hyperuricemic hypertension will be critical in determining whether treatment of hyperuricemia is beneficial to treating obesity-mediated hypertension.

Elevated XO activity, uric acid levels, and cytokines are known to correlate with obesity. Studies have demonstrated that cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), regulate XO expression.6 Mechanistically, weight loss has also been shown to reduce the elevated cytokine levels and inflammation seen in obese adolescents.7 Therefore, changes in the levels of cytokines after weight loss may lead to changes in XO activity and blood pressure. It is still not known whether obesity drives increases in XO and uric acid. Studying the effect of weight loss on XO activity, uric acid, and blood pressure will provide greater insight into one potential mechanism of how obesity increases cardiovascular risk. Additionally, investigating this question in a pediatric population allows for the examination of the effect of weight loss on uric acid mediated changes in blood pressure before chronic hypertension has developed.

Since meal replacement therapy has been demonstrated to be an effective short-term weight loss therapy in adolescents,8 it was chosen as our model to determine if weight loss mediated changes in uric acid levels are associated with changes in blood pressure. Therefore the primary objective of this study was to determine if modest weight loss in youth with severe obesity would reduce blood pressure via changes in XO activity and plasma uric acid levels. As secondary objectives, we investigated the role of changes in cytokine levels on XO activity. We hypothesized that weight reduction would result in decreased cytokines which in turn would decrease XO activity. Decreased XO activity would lead to decreased uric acid which in turn would result in decreased blood pressure.

Methods

This was an ancillary study within the context of a larger clinical trial in which 16 adolescents (mean age 15 ± 2 years) received meal replacement therapy for 4 weeks. …

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