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1 Medicine-Nephrology, University of Florida, Gainesville, FL, USA
* To whom correspondence should be addressed. E-mail: nakagt{at}medicine.ufl.edu.
The worldwide epidemic of the metabolic syndrome correlates with an elevation in serum uric acid as well as a marked increase in total fructose intake (in the form of table sugar and high fructose corn syrup). Fructose raises uric acid, the latter which inhibits nitric oxide bioavailability. Since insulin requires nitric oxide to stimulate glucose uptake, we hypothesized that fructose-induced hyperuricemia may have a pathogenic role in the metabolic syndrome. Four sets of experiments were performed. First, pair feeding studies showed that fructose, and not dextrose, induced features (hyperinsulinemia, hypertriglyceridemia, and hyperuricemia) of the metabolic syndrome. Second, in rats receiving high fructose diet, the lowering of uric acid with either allopurinol (a xanthine oxidase inhibitor) or benzbromarone (a uricosuric agent) were able to prevent or reverse features of the metabolic syndrome. In particular, the administration of allopurinol prophylactically prevented fructose induced hyperinsulinemia (272.3 vs.160.8 pmol/L, p<0.05), systolic hypertension (142 vs. 133 mmHg, p<0.05), hypertriglyceridemia (233.7vs. 65.4 mg/dl, p<0.01) and weight gain (455 vs. 425 g, p<0.05) at 8 weeks. Neither allopurinol nor benzbromarone affected dietary intake of control diet in rats. Finally, uric acid dose-dependently inhibited endothelial function as manifested by a reduced vasodilatory response of aortic artery rings to acetylcholine. These data provide the first evidence that uric acid may be a cause of the metabolic syndrome, possibly due to its ability to inhibit endothelial function. Fructose may have a major role in the epidemic of metabolic syndrome and obesity due to its ability to raise uric acid.
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