Amelioration of High Fructose Diet-Induced Insulin Resistance, Hyperuricemia, and Liver Oxidative Stress by Combined Use of Selective Agonists of PPAR-α and PPAR-γ in Rats

Abstract

Background: The use of high-fructose (Fr) corn sweeteners and sucrose in manufactured food has markedly increased recently. This excessive Fr intake has been proposed in the etiology of the metabolic syndrome, which shows an increasing prevalence throughout the world. Objective: In this study, we questioned whether fenofibrate (FF), a peroxisome proliferator-activated receptor (PPAR)-α agonist, and pioglitazone (PG), a PPAR-γ agonist, might be effective in ameliorating the metabolic syndrome in a rat model. Materials and Methods: The metabolic syndrome was induced by feeding rats a high-Fr (60%) diet for 10 weeks. The rats were divided into 5 groups: control group, fed a normal rat chow; Fr + vehicle group; Fr + FF group; Fr + PG group; and Fr + (FF + PG) group (treated with both drugs). Drug or vehicle treatment was given daily for 6 weeks (from weeks 5 to 10). Thereafter, blood and liver samples were obtained for biochemical studies. Results: Rats fed a high-Fr diet developed hyperglycemia, hyperinsulinemia, hyperuricemia, hypertriglyceri demia, and hypercholesterolemia, and had increased serum alanine aminotransferase, hepatic tumor necrosis factor-α, and malondialdehyde levels but decreases in both glutathione content and superoxide dismutase activity. Rat treatment with FF and/or PG attenuated these alterations. The improvement was greater with the combined treatment than with either drug alone, and normalization of insulin sensitivity was observed only in rats treated with the combination therapy. Conclusion: Acting on the 2 main PPAR subfamilies, the combination of FF and PG provides a more efficacious therapy for modulating the changes in serum insulin, uric acid, and lipids, as well as the accompanying hepatic inflammation and oxidative stress that characterize the Fr-induced metabolic syndrome.

Tert‐butylhydroquinone abrogates fructose‐induced insulin resistance in rats via mitigation of oxidant stress, NFkB‐mediated inflammation in the liver but not the skeletal muscle of high fructose drinking rats

“…In this study, administration of high fructose drinking water to the disease group increased their hepatic SOD activity and MDA concentrations but decreased their hepatic CAT activity, suggesting fructose‐induced hepatic oxidative stress. Similar reports on the induction of hepatic oxidative stress following administration of high fructose diets in rats were also given by Francini et al (2010) ; Prabhakar et al (2014) and Farag et al (2020), respectively.…”

“…Insulin resistance refers to the decreased ability of target tissues, such as liver, adipose, and muscle, to properly respond to normal or increased concentrations of insulin in circulation (Ferrier, 2014). Excess or regular intake of fructose contributes to insulin resistance development through fructose‐mediated induction of oxidative stress and inflammation (Farag et al, 2020; Horst & Serlie, 2017; Jaiswal et al, 2015).…”

“…Excess or regular intake of fructose contributes to insulin resistance development through fructose-mediated induction of oxidative stress and inflammation (Farag et al, 2020;Horst & Serlie, 2017;Jaiswal et al, 2015).…”

Cytokine modulation by etanercept ameliorates metabolic syndrome and its related complications induced in rats administered a high-fat high-fructose diet

“…One of the most prominent pathological features of MS correlated with the diagnostic conditions of human MS is IR 50 . In the present study, HFHF administration resulted in IR, as characterized by the elevated HOMA-IR score.…”

“…The suppressing effect of TNF-α upon liver insulin action is achieved by interrupting insulin signaling via serine phosphorylation of insulin receptor proteins 50 , 51 . Accordingly, in the present study, the neutralization of TNF-α by ETA enhanced insulin sensitivity as indicated by the normalized HOMA-IR and significantly reduced fasting glucose and insulin serum levels compared with those in the HFHF group.…”