Mice Heterozygous for the Xanthine Oxidoreductase Gene Facilitate Lipid Accumulation in Adipocytes

Abstract

Objective-Xanthine oxidoreductase (XOR) catalyzes the production of uric acid with concomitant generation of reactive oxygen species. XOR has been shown to regulate adipogenesis through the control of peroxisome proliferator-activated receptor γ, but its role in adipose tissue remains unclear. The aim of this study was to examine the role of XOR in adipose tissue using XOR genetically modified mice. Approach and Results-Experiments were performed using 2-, 4-, and 18-month-old XOR heterozygous mice (XOR +/− ) and their wild-type littermates to evaluate the physiological role of XOR as the mice aged. Stromal vascular fraction cells were prepared from epididymal white adipose tissue in 2-month-old XOR mice to assess adipogenesis. At 18 months, XOR +/− mice had significantly higher body weight, higher systolic blood pressure, and higher incidence of insulin resistance compared with wild-type mice. At 4 months, blood glucose and the expressions of CCAAT enhancer-binding protein β, peroxisome proliferator-activated receptor γ, monocyte chemoattractant protein-1, and tumor necrosis factor α mRNA in epididymal white adipose tissue were significantly higher in XOR +/− than in wild-type mice. Furthermore, histological analysis of epididymal white adipose tissue in XOR +/− mice revealed that adipocyte size and the F4/80-positive macrophage count were increased. Experiments with a high-fat diet exhibited that body weight gain was also significantly higher in XOR +/− than in wild-type mice. In stromal vascular fraction cells derived from XOR +/− mice, the levels of peroxisome proliferator-activated receptor γ, fatty acid-binding protein 4, and CCAAT enhancer-binding protein α mRNA were upregulated, and oxidative stress levels were elevated during differentiation into adipocytes. Conclusions-These results suggest that the reduction in XOR gene expression in mice augments lipid accumulation in adipocytes, accompanied by an increase in oxidative stress, and induces obesity with insulin resistance in older age.

Uric acid as a modulator of glucose and lipid metabolism

“…These experiments suggest that the uric acidinduced inhibition of adiponectin production is not mediated through redox-dependent signalling, but rather through a mechanism involving PPAR-g [27]. Similarly, the level of adiponectin mRNA is decreased in the epididymal adipose tissue of xanthine oxidoreductase heterozygous knockout mice [62]. It has been previously suggested that xanthine oxidoreductase is required for the activation of PPAR-g [Cheung 2007].…”

“…Indeed, xanthine oxidoreductase heterozygous knockout mice at 18 months of age show an increase in oxidative stress levels, characterised by the production of malondialdehyde and H 2 O 2 , accompanied by the increased expression of MCP-1 mRNA in epididymal adipose tissue [62]. However, the effect of uric acid on adiponectin production is not inhibited in the presence of superoxide scavengers or inhibitors of NADPH oxidase, while the addition of rosiglitazone in the incubation medium restored adiponectin mRNA expression and adiponectin levels to control levels [27].…”

The Growing Problem of Obesity

“…Murakami and colleagues showed that mice heterozygous for the xanthine oxidoreductase gene, which catalyzes the production of uric acid, displayed increased lipid accumulation in adipocyte along with increased oxidative stress. These mice also displayed higher body weight, systolic blood pressure and insulin resistance versus the wild-type controls 26 . Epididymal white adipose tissue displayed increased adipocyte size and greater macrophage content (F4/80 immunostaining) versus the wild-type controls.…”

Mixed-lineage kinase 3 pharmacological inhibition attenuates murine nonalcoholic steatohepatitis

“…Inc.). HOMA-IR was calculated by using the following formula: HOMA-IR = 26 × fasting insulin level (ng/ml) × fasting glucose level (mg/dl)/405 (45). Mice were sacrificed under general anesthesia by ketamine/xylazine cocktail (83 mg/kg ketamine/16 mg/kg xylazine, i.p.)…”