Early Effects of a Low Fat, Fructose-Rich Diet on Liver Metabolism, Insulin Signaling, and Oxidative Stress in Young and Adult Rats

Abstract

The increase in the use of refined food, which is rich in fructose, is of particular concern in children and adolescents, since the total caloric intake and the prevalence of metabolic syndrome are increasing continuously in these populations. Nevertheless, the effects of high fructose diet have been mostly investigated in adults, by focusing on the effect of a long-term fructose intake. Notably, some reports evidenced that even short-term fructose intake exerts detrimental effects on metabolism. Therefore, the aim of this study was to compare the metabolic changes induced by the fructose-rich diet in rats of different age, i.e., young (30 days old) and adult (90 days old) rats. The fructose-rich diet increased whole body lipid content in adult, but not in young rats. The analysis of liver markers of inflammation suggests that different mechanisms depending on the age might be activated after the fructose-rich diet. In fact, a pro-inflammatory gene-expression analysis showed just a minor activation of macrophages in young rats compared to adult rats, while other markers of low-grade metabolic inflammation (TNF-alpha, myeloperoxidase, lipocalin, haptoglobin) significantly increased. Inflammation was associated with oxidative damage to hepatic lipids in young and adult rats, while increased levels of hepatic nitrotyrosine and ceramides were detected only in young rats. Interestingly, fructose-induced hepatic insulin resistance was evident in young but not in adult rats, while whole body insulin sensitivity decreased both in fructose-fed young and adult rats. Taken together, the present data indicate that young rats do not increase their body lipids but are exposed to metabolic perturbations, such as hepatic insulin resistance and hepatic oxidative stress, in line with the finding that increased fructose intake may be an important predictor of metabolic risk in young people, independently of weight status. These results indicate the need of corrective nutritional interventions for young people and adults as well for the prevention of fructose-induced metabolic alterations.

Heterogeneity in Metabolic Responses to Dietary Fructose

“…Investigations of the relationship between SSB intake and metabolic responses have also shown a statistically significant rise in blood pressure with fructose ingestion in healthy adults (Cai et al, 2018). Similar findings are also corroborated in fructose-fed animal studies (Nakagawa et al, 2006; Crescenzo et al, 2018). According to Johnson et al (2007), fructose-induced hyperuricemia may contribute to endothelial dysfunction and increased risk of hypertension.…”

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“…Intensive sugar consumption is increasingly measured as a key contributor to the worldwide epidemics of obesity and diets high in fructose have been shown to produce all of the key features of obesity and metabolic syndrome 23,24,25,26,27 , which is becoming a leading cause of death globally 28 . There is an obvious interplay of various factors in the onset and progression of obesity, however, metabolism being a crucial one plausibly due to sedentary or so-called modern lifestyles and thus has become a matter of immediate concern.…”

Fat and Sugar—A Dangerous Duet. A Comparative Review on Metabolic Remodeling in Rodent Models of Nonalcoholic Fatty Liver Disease

“…The evaluation of the oxidative stress response through the progression of the disease represents a challenge to merge features of NAFLD patients and mouse models and provide mechanistic insights and therapeutic opportunities (see Table 4). High-fructose diet [269] Mitochondrial ROS production Lipid peroxidation High-fat and high-fructose diet [270] Superoxide generation Mitochondrial NADPH oxidase 4 (NOX4) High-fat and high-sucrose diet [167] Lipid peroxidation Copper deficient diet [271] Obesity has been widely studied in recent decades, and a close connection between excessive body weight and ROS overproduction has been established [272]. A high-fat low-carbohydrate diet leads to impaired mitochondrial function and increased cellular oxidative damage [273].…”

“…Fructose and sucrose are also considered major mediators of NAFLD. A low-fat, fructose-rich diet results in marked oxidative stress levels in hepatocytes [269]. Moreover, García-Berumen et al demonstrated that the supplementation of a HF diet with fructose induces more severe hepatic damage as shown by the inhibition of state 3 and the impairment of Complex I activity, which subsequently promotes further mitochondrial ROS production [270].…”