Obesity is often accompanied by hyperuricemia. However, purine metabolism in various tissues, especially regarding uric acid production, has not been fully elucidated. Here we report, using mouse models, that adipose tissue could produce and secrete uric acid through xanthine oxidoreductase (XOR) and that the production was enhanced in obesity. Plasma uric acid was elevated in obese mice and attenuated by administration of the XOR inhibitor febuxostat. Adipose tissue was one of major organs that had abundant expression and activities of XOR, and adipose tissues in obese mice had higher XOR activities than those in control mice. 3T3-L1 and mouse primary mature adipocytes produced and secreted uric acid into culture medium. The secretion was inhibited by febuxostat in a dose-dependent manner or by gene knockdown of XOR. Surgical ischemia in adipose tissue increased local uric acid production and secretion via XOR, with a subsequent increase in circulating uric acid levels. Uric acid secretion from whole adipose tissue was increased in obese mice, and uric acid secretion from 3T3-L1 adipocytes was increased under hypoxia. Our results suggest that purine catabolism in adipose tissue could be enhanced in obesity.
Myc has emerged as a pivotal transcription factor for four metabolic pathways: aerobic glycolysis, glutaminolysis, polyamine synthesis, and HIF-1a/mTOR. Each of these pathways accelerates the utilization of sugar. The BCG vaccine, a derivative of Mycobacteria-bovis, has been shown to trigger a long-term correction of blood sugar levels to near normal in type 1 diabetics (T1D). Here we reveal the underlying mechanisms behind this beneficial microbe-host interaction. We show that baseline glucose transport is deficient in T1D monocytes but is improved by BCG in vitro and in vivo. We then show, using RNAseq in monocytes and CD4 T cells, that BCG treatment over 56 weeks in humans is associated with upregulation of Myc and activation of nearly two dozen Myc-target genes underlying the four metabolic pathways. This is the first documentation of BCG induction of Myc and its association with systemic blood sugar control in a chronic disease like diabetes.
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