A causal role for uric acid in fructose-induced metabolic syndrome.
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.
Nakagawa
Takahiko
T
Division of Nephrology, Hypertension, and Transplantation, PO Box 100224, University of Florida, Gainesville, FL 32610, USA. nakagt@medicine.ufl.edu
Hu
Hanbo
H
Zharikov
Sergey
S
Tuttle
Katherine R
KR
Short
Robert A
RA
Glushakova
Olena
O
Ouyang
Xiaosen
X
Feig
Daniel I
DI
Block
Edward R
ER
Herrera-Acosta
Jaime
J
Patel
Jawaharlal M
JM
Johnson
Richard J
RJ
D000818:Animals; D005632:Fructose / Q000633:toxicity*; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood* / Q000139:chemically induced; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000097:blood; D014527:Uric Acid / Q000097:blood*
D014280:Triglycerides; D014527:Uric Acid; D005632:Fructose