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A causal role for uric acid in fructose-induced metabolic syndrome

Takahiko Nakagawa,¹ Hanbo Hu,¹ Sergey Zharikov,¹ Katherine R. Tuttle,² Robert A. Short,^2,3 Olena Glushakova,¹ Xiaosen Ouyang,¹ Daniel I. Feig,⁴ Edward R. Block,¹ Jaime Herrera-Acosta,^5, Jawaharlal M. Patel,¹ and Richard J. Johnson¹

¹Division of Nephrology, Hypertension, and Transplantation, University of Florida, Gainesville, Florida; ²Department of Research, The Heart Institute of Spokane, and ³Biostatistics, Washington State University, Spokane, Washington; ⁴Division of Nephrology-Medicine, Baylor College of Medicine, Houston, Texas; and ⁵Departamento de Nefrologia, Instituto Nacional de Cardiologia Ignacio Chavez, Tlalpan, Mexico

Submitted 6 April 2005 ; accepted in final form 26 September 2005

The worldwide epidemic of 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, and the latter inhibits nitric oxide bioavailability. Because insulin requires nitric oxide to stimulate glucose uptake, we hypothesized that fructose-induced hyperuricemia may have a pathogenic role in 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 metabolic syndrome. Second, in rats receiving a high-fructose diet, the lowering of uric acid with either allopurinol (a xanthine oxidase inhibitor) or benzbromarone (a uricosuric agent) was able to prevent or reverse features of 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 (233.7 vs. 65.4 mg/dl, P < 0.01), and weight gain (455 vs. 425 g, P < 0.05) at 8 wk. 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 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.

obesity; insulin resistance

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