Long-Term Dietary Fructose Causes Gender-Different Metabolic and Vascular Dysfunction in Rats: Modulatory Effects of Resveratrol

Abstract

Background/Aims: There is limited knowledge on the gender differences in the effects of dietary fructose. In the current study, we investigated whether long-term fructose intake impacts metabolic parameters and vascular reactivity differently between male and female rats. Moreover, we tested whether resveratrol has a gender-specific effectiveness on the alterations. Methods: Male and female rats were divided into four groups as control; resveratrol; fructose and resveratrol plus fructose. Fructose was given to the rats as 10% solution in drinking water for 24 weeks. All rats were fed with the standard diet with or without resveratrol. Results: High-fructose diet increased plasma insulin, triglyceride and VLDL levels as well as omental weights in both genders. Long-term dietary fructose causes marked increase in body weight of males, but not females. Dietary fructose impaired endothelial relaxation to acetylcholine and intensified contraction to phenylephrine in the aortas of male and female rats, but differently it also reduced insulin-induced vasodilation in aortas of female rats. These changes were associated with decreased expression levels of endothelial nitric oxide synthase (eNOS) mRNA and protein, but increased in inducible NOS (iNOS), in aortas of male and female rats. Dietary fructose suppressed expression levels of sirtuin 1 (SIRT1) and insulin receptor substrate-2 (IRS-2) mRNA in aortas from female rats. Resveratrol supplementation efficiently restored fructose-induced metabolic and vascular dysfunction in both genders probably by regulating eNOS and iNOS production. Moreover, the augmentations in SIRT1 and IRS-2 mRNA in females and IRS-1 mRNA in males may possibly contribute to the beneficial effects of resveratrol as well. Conclusion: Long-term fructose intake may differently affect metabolic and vascular function between male and female rats, which are modified by resveratrol.

Naringin ameliorates endothelial dysfunction in fructose-fed rats

“…It has been reported that endothelium-derived NO is a predominant mediator of endothelial-dependent relaxation in aortae, and its bioavailability is impaired in several pathophysiological states such as hyperlipidemia, metabolic syndrome, diabetes and hypertension (35,36). There is increasing evidence that high fructose induced endothelial dysfunction is associated with the decreased NO bioavailability in the vasculature (8,12).…”

“…Therefore, in our study, nitrotyrosine was detected to indirectly indicate ROS mediated NO inactivation and peroxynitrite formation. It has been reported that fructose-fed rats exhibited a decreased expression of eNOS and p-eNOS in several tissues including aorta (8,42,43). In addition fructose has been demonstrated to generate peroxynitrite through increased superoxide production and enhanced methyglyoxal formation (16).…”

“…Reduction of NO bioavailability, caused by reduced eNOS activity and/or accelerated NO degradation, results in impaired endothelium-dependent vasorelaxation, increased thrombus formation, and progressive atherogenesis (7). There is growing evidence that fructose fed animals exhibited impaired endothelium-dependent relaxation (8)(9)(10)(11) and decreased NO bioavailability (12)(13)(14). High fructose consumption is also reported to induce oxidative and nitrative stress in vascular tissues and that oxidative/nitrative stress seems to play a major role in endothelial dysfunction.…”

“…Indeed, elevated levels of reactive oxygen species (ROS) cause a decrease in bioavailability of NO and an increase in production of powerful oxidant peroxynitrite that induces eNOS inactivation (15,16). A number of studies reported that decreased eNOS expression and increased nitrotyrosine expression were found in aortae from fructose fed rats (8,17,18). Therefore, the increased oxidative stress and the decreased NO synthesis have been proposed to be involved in high fructose-induced endothelial dysfunction.…”

SIRT1 Regulates the Inflammatory Response of Vascular Adventitial Fibroblasts through Autophagy and Related Signaling Pathway

“…The SIRT1 activator resveratrol (RSV) attenuated vascular endothelial inflammation and improved vascular function by inducing autophagy [11, 12], while SIRT1 inhibitor sirtinol promoted the inflammatory response of human THP-1 cells through inhibition of autophagy [13]. A recent study showed that fenofibrate prevented high glucose-induced inflammatory response in cardiac myoblasts by upregulating SIRT1-mediated autophagy [14].…”