The effect of obesity and high fat diet on cardiovascular risk and intestinal drug metabolism

Introduction: Childhood obesity is a major epidemic for many industrialized countries, especially in countries where a high fat diet is prevalent. The purpose of this thesis was to examine the effect of obesity and high fat diet on cardiovascular risk factors (e.g. xanthine oxidase activity and uric acid formation) and on small intestinal drug metabolism.;Methods: An assay measuring the production of 7-hydroxy-lumazine was developed as a probe for xanthine oxidase activity. This lumazine assay was used to study xanthine oxidase as a risk factor for cardiovascular disease in obese children compared to normal-weight children, and this assay was also utilized to study xanthine oxidase activity in obese adolescents before and after weight loss to determine xanthine oxidase's role in mediating changes in blood pressure due to weight loss. In order to study the effects of obesity and high fat diet on small intestinal drug metabolism, UGT activity was assessed in a rat model of diet-induced obesity using in vitro phenotyping methodologies.;Results: Plasma xanthine oxidase activity was increased in obese children and was associated with BMI z-score and waist circumference, but was not associated with blood pressure. Weight loss via meal replacement therapy led to decreases in both uric acid production and excretion, but no significant change in plasma levels. Increases in UGT activity were observed in both obesity resistant and obesity prone rats when they were fed a high fat diet, even though the obesity resistant rats didn't gain a significant amount of weight when fed a high fat diet. Conclusions: Changes in xanthine oxidase activity and intestinal UGT activity may be due to changes to diets and gut microbiota. High fat diets have been shown to alter the gut microbiota and increase plasma LPS levels. Therefore, a high fat diet and not obesity may be responsible for both the changes in xanthine oxidase and UGT activities, and future studies on obesity and CVD risk or alterations in drug metabolizing enzymes should focus on monitoring diets and changes to the gut microbiota.