189 - Hepatic-specific ablation or whole-body inhibition of xanthine oxidase in mice corrects obesity-induced systemic hyperuricemia without improving metabolic abnormalities

Abstract

Rationale: Systemic hyperuricemia (HyUA) in obesity/T2DM, facilitated by elevated xanthine oxidase (XO) activity, which is the sole source of UA in mammals, has been proposed to contribute to the pathogenesis of insulin resistance/dyslipidemia in obesity. However, this hypothesis has not been assessed directly. Objectives The effects of tissue-specific, genetic ablation of XO (a liver-specific knockout (LXO)) and whole-body pharmacologic inhibition of XO (febuxostat (FEBUX)) on obesity-induced insulin resistance/dyslipidemia were assessed. Findings Deletion of hepatic XO substantially lowered liver and plasma UA levels. When exposed to an obesogenic diet LXO and floxed (FLX, control) mice became equally obese. However, unlike obese floxed, liver and systemic HyUA in LXO mice was absent. Despite this, obese LXO mice became as insulin resistant and dyslipidemic as obese FLX mice. In obese C57BL/6J mice, FEBUX dramatically lowered plasma and tissue UA and XO activity compared to vehicle controls (CONT). However, obesity-associated insulin resistance/dyslipidemia were similar in FEBUX and CONT. Furthermore, neither pharmacologic inhibition nor hepatic ablation of XOR significantly altered indices of oxidant stress in the liver at 20 weeks of high-fat feeding compared with untreated controls. Conclusions These data demonstrate that liver XO expression is a critical determinant of blood UA homeostasis; that deletion of liver XO is sufficient to prevent the systemic HyUA of obesity, and that neither prevention nor correction of HyUA improve insulin resistance/dyslipidemia in obesity or diminish liver oxidant load. Thus, systemic HyUA, while clearly a biomarker of the metabolic abnormalities of obesity, does not appear to be a causative factor.