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

Abstract

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.

Fructose and metabolic diseases: New findings, new questions

“…Because insulininduced glucose utilization involves not only the stimulation of key metabolic pathways in insulin-sensitive cells but also a NO-dependent increase in muscle blood flow [41], it was proposed that inhibition of the vascular effects of insulin by uric acid was involved in fructose-induced insulin resistance. In support of this hypothesis the development of insulin resistance was prevented by lowering uric acid concentrations with an uricosuric agent in fructose-fed rats [42]. …”

Impact of different adiposity measures on the relation between serum uric acid and blood pressure in young adults

“…Masuo et al 4 showed that SUA predicts weight gain in humans and experimental animal studies have shown that allopurinol (a SUA-lowering drug) prevents both fructose-induced hyperuricaemia and weight gain. 23 Based on these results, it is difficult to differentiate whether hyperuricemia directly causes obesity or both hyperuricemia and obesity share a common cause, that is, increased fructose intake. Thus, it could be that obesity is in the causal pathway between SUA and BP and controlling for adiposity would explain the attenuation seen in the effect sizes.…”

The planetary biology of ascorbate and uric acid and their relationship with the epidemic of obesity and cardiovascular disease

“…In addition to raising blood pressure, recent studies support uric acid as having a role in insulin resistance and obesity [ 88,89 ]. Indeed, fructose, which rapidly raises uric acid, induces metabolic syndrome in animals and this can be ameliorated by lowering uric acid [ 88 ].…”

“…There are now extensive studies showing that a high uric acid independently predicts the development of hypertension [82][83][84]; likewise, an elevated uric acid is common in early hypertension and was present in almost 90% of hypertensive adolescents in one study [ 85 ]. Furthermore, recent clinical trials have found that lowering uric acid lowers blood pressure in both adolescents and adults with hypertension (and D Feig and R Johnson, unpublished)[ 86,87 ].In addition to raising blood pressure, recent studies support uric acid as having a role in insulin resistance and obesity [ 88,89 ]. Indeed, fructose, which rapidly raises uric acid, induces metabolic syndrome in animals and this can be ameliorated by lowering uric acid [ 88 ].…”