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 (2. P < 0. 0. 5), systolic hypertension (1. Hg, P < 0. 0. 5), hypertriglyceridemia (2. P < 0. 0. 1), and weight gain (4. ![]() P < 0. 0. 5) 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. The prevalence of metabolic syndrome is increasing and now affects 2. United States (1. The epidemic correlates with pronounced changes in the environment, behavior, and lifestyle and is considered one of the main threats to human health worldwide. A diet high in fructose can increase uric acid levels, but allopurinol may help. Hypertension A diet high in. Uric Acid: Potential Role in Hypertension and. Uric acid was first associated with primary hypertension in 1874, yet its role in this condition remains unclear. Historically, uric acid was thought to be. Excessive fructose intake induces the features of. Metabolic syndrome confers a greater than threefold increased risk for cardiovascular mortality (2. It is thus critical to identify mechanisms and strategies for preventing or treating this serious health problem. As obesity and type 2 diabetes have escalated to epidemic proportions (2. The last 2. 5 years have witnessed a marked increase in total per capita fructose intake, primarily in the form of sucrose (a disaccharide consisting of 5. HFCS; 5. 5% fructose content) (3). Fructose intake is linked to the epidemic of obesity and diabetes (2. Soft drink intake (high in HFCS) is associated with an increased risk for obesity in adolescents (2. Uric Acid in Hypertension and Cardiovascular and. Hyperuricemia Treatment & Management. The diagnosis is based on the identification of uric acid. Diagnosis and Management of Gout. ![]() Excess fruit juice (also rich in fructose) is associated with the development of obesity in children (8). Fructose- fed rats also develop features of metabolic syndrome (1. One distinction between fructose and glucose is that fructose raises serum uric acid (3. Elevated serum uric acid predicts the development of obesity and hypertension (2. This raised the possibility that uric acid may have a pathogenetic role in metabolic syndrome. In the current study, we show that fructose- induced metabolic syndrome is partially prevented by lowering serum uric acid in the rat. The reduction of endothelial nitric oxide (NO) bioavailability by uric acid may be a mechanism for insulin resistance and hypertension. METHODSIn Vivo Studies. ![]() Experiment I: treatment of fructose- induced hyperuricemia with allopurinol. Male Sprague- Dawley rats (1. Harlan, Madison, WI, n = 1. ![]() ![]() The control diet contained 4. The caloric content of these diets are 3. At 4 wk, blood samples were obtained at 1. AM after 4 h of fasting. One- half of the fructose- fed rats were administered allopurinol (1. Sigma, St. Louis, MO) for an additional 6 wk to lower serum uric acid. Fresh drinking water containing allopurinol was replaced every 2 days. Rats were divided into three groups: control, fructose, and fructose+allopurinol. At 1. 0 wk, an oral glucose tolerance test (OGTT) was performed, in which rats were fasted overnight (1. Blood was sampled at 0, 3. The rats were then killed. Experiment II: prevention of fructose- induced hyperuricemia with allopurinol. To assess the effect of preventing hyperuricemia during the period of the study, allopurinol was initiated on the day when the fructose diet was given (from week 0 to week 8). Three groups (control, fructose, and fructose+allopurinol; n = 8 each) were designed for this prevention study. Body weight was measured every 2 wk. Food consumption was measured for 3 days at 8 wk. Experiment III: effect of lowering of uric acid by either allopurinol or benzbromarone on body weight and food consumption. In this experiment, the effect of benzbromarone, a uricosuric agent (1. Sigma), was also examined to confirm the effect of lowering of uric acid on body weight and food intake. Fresh drinking water containing benzbromarone was replaced every 2 days. Three groups (control, allopurinol, and benzbromarone; n = 8 each) were studied. All groups were fed with the control diet for 8 wk. Body weight and the consumption of food were measured weekly for 8 wk. Experiment IV: comparison between 6. Rats were pair- fed with a 6. Because experiment II showed that each rat normally eats 2. At 4 wk, total food intake per animal was calculated from the food left over. Total food intake is the subtraction of the leftover food from the total food administered (1,4. In addition to the above two groups, a third group of fructose- fed rats was administered benzbromarone. Their body weight was measured weekly. At 4 wk, after 5 h of fasting, insulin, triglyceride, and uric acid were measured. All protocols were approved by the Animal Care Committee of the University of Florida. Measurements. Systolic blood pressure was assessed as the mean value of three consecutive measurements obtained in the morning using a tail- cuff sphygmomanometer (Visitech BP2. Visitech Systems, Apex, NC). All animals were preconditioned for blood pressure measurements 1 wk before each experiment. Serum uric acid was measured by the uricase method. Blood glucose was measured with the ONE TOUCH system (Johnson& Johnson, Milpitas, CA). Rat insulin was measured by ELISA (Crystal Chem, Chicago, IL). The insulin sensitivity index was calculated using the formula of Matsuda and De. Fronzo . Serum lipids were measured with an autoanalyzer (VETAce, Alfa Wassermann, West Caldwell, NJ) or a Triglyceride- SL assay kit (Diagnostic Chemicals, Charlottetown, PE, Canada). Vasorelaxation of Rat Aortic Artery Segments. Rat aortic artery (AA) segments (1- to 0. After 1- h equilibration of resting force of 1. AA segment was confirmed by monitoring 0. After being washed several times, the segments were incubated with various concentrations of uric acid (0–1. Stable construction was induced by 0. The vascular tensions were continuously monitored with an isometric force transducer (Harvard Apparatus, Holliston, MA). To standardize the data, the U- 4. Statistical Analysis. All values presented are expressed as means . Significance was defined as P < 0. RESULTSIn Vivo Studies. Serum uric acid levels, systolic blood pressure, and fasting insulin levels were elevated in fructose- fed rats compared with rats fed a control diet at 4 wk (Table 1). In addition, the body weight of fructose- fed rats tended to increase compared with rats fed a normal diet (Table 1). These data demonstrate that fructose feeding induces early features of metabolic syndrome in rats. Table 1. Experiment I: general characteristics of control and fructose groups at 4 wk. To examine the role of uric acid in this model, one- half of the fructose- fed rats were treated with allopurinol (a xanthine oxidase inhibitor) for 6 additional wk. This treatment was effective at lowering uric acid, whereas the fructose- fed rats that did not receive treatment continued to be hyperuricemic (Fig. In addition, we examined the urinary excretion of uric acid in these animals to clarify the mechanisms of hyperuricemia in fructose- fed rats. B, fructose- fed rats had a lower urinary excretion of uric acid. Interestingly, allopurinol prevented the reduced excretion of uric acid in fructose- fed rats. Fig. 1. Effects of allopurinol (AP) treatment for hyperuricemia on metabolic parameters in fructose- fed (Fr) rats. A: Fr rats are hyperuricemic at 9 wk, and this is prevented by AP (1. B: Fr reduced urinary excretion of UA at 9 wk, and this is prevented by AP. C: hypertension develops in Fr rats, which is significantly reduced by AP. D: serum triglycerides (TG) are increased in Fr rats, and this is completely prevented by AP. E: serum triglyceride level correlates directly with the serum UA. Fructose- fed rats treated with allopurinol showed an improvement in metabolic syndrome. Allopurinol significantly reduced systolic blood pressure in fructose- fed rats (Fig. C), although pressures remained higher than that observed in control rats. Fructose- fed rats also developed marked hypertriglyceridemia that was abolished by allopurinol treatment (Fig. The reduction in serum uric acid correlated directly with the decrease in triglyceride levels (Fig. Fructose- fed rats also showed an increase in body weight compared with controls. Allopurinol prevented the increase in body weight, although this did not reach significance (5. A), fructose- fed rats developed fasting hyperinsulinemia that was reversed with allopurinol (Fig. Postprandial hyperinsulinemia also occurred in fructose- fed rats administered an OGTT, and this was partially but significantly lower in allopurinol- treated rats (Fig. B), resulting in improved insulin sensitivity (Fig. Effect of AP treatment on glucose metabolism in Fr rats. A: glucose tolerance test at 1. Similar blood glucose levels were observed in all groups. B: plasma insulin levels following the glucose tolerance test. Fructose ingestion was associated with fasting and postprandial hyperinsulinemia. AP (1. 50 mg/l) prevented basal hyperinsulinemia and significantly reduced postprandial hyperinsulinemia.
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