Chronic Consumption Of Fructose Research Articles

Maternal exercise during pregnancy modulates genotoxicity caused by high fructose consumption in mice offspring.

Pregnancy is a period that is characterized by several metabolic and physiological changes and requires special attention, especially with regard to the relationship between feeding and foetal development. Therefore, the objective of this study was to evaluate whether the practice of voluntary physical exercise (VPE) in combination with chronic consumption of fructose (FRU) from the beginning of life and/or until the gestational period causes genotoxic changes in pregnant females and in their offspring. Seventy Swiss female mice received FRU in the hydration bottle and/or practiced VPE for 8 weeks (prepregnancy/pregnancy). After the lactation period, the offspring groups were separated by sex. It was observed that the consumption of FRU affected the food consumption, serum concentration of FRU, and glycemic profile in the mothers and that the VPE decreases these parameters. In addition, FRU was genotoxic in the mothers' peripheral tissues and VPE had a preventive effect on these parameters. The offspring showed changes in food consumption, serum FRU concentration, and body weight, in addition to an increase in the adiposity index in male offspring in the FRU (FRU) group and a decrease in the FRU + VPE group. FRU leads to hepatic steatosis in the offspring and VPE was able to decrease the area of steatosis. In addition, FRU led to genotoxicity in the offspring and VPE was able to modulate this effect, reducing damages. In conclusion, we observed that all interventions with VPE had nutritional, genetic, and biochemical benefits of the mother and her offspring.

The chronic consumption of dietary fructose promotes the gut Clostridium species imbalance and bile acid alterations in developing nonalcoholic fatty liver disease

Excessive fructose intake is associated with the rising prevalence of nonalcoholic fatty liver disease (NAFLD). The gut microbiome (GM) and bile acids (BAs) are involved in the pathogenesis of NAFLD, but the impact of fructose on their cross-talk is unclear. In this study, adult male C57BL/6J mice were fed a normal diet with tap water (ND) or with 4% fructose in the drinking water (Fru), 60% high-fat diet with tap water (HF) or with 4% fructose solution (HFF) for 12 weeks. Targeted BA analysis was performed in five anatomical sites including the liver, ileum contents, portal serum, cecum contents, and feces. Metagenomic sequencing was performed to explore gut dysbiosis. Within 12 weeks, the 4% fructose diet could initially stimulate gut dysbiosis and BA upregulation in the ileum, portal serum, and cecum when the intestinal and hepatic transport system remained stable without hepatic lipid accumulation. However, the chronic consumption of fructose promoted HF-induced NAFLD, with significantly increased body weight, impaired glucose tolerance, and advanced liver steatosis. BA transporters were inhibited in HFF, causing the block of internal BA circulation and increased BA secretion via cecum contents and feces. Notably, lithocholic acid (LCA) and its taurine conjugates were elevated within the enterohepatic circulation. Meanwhile, the Clostridium species were significantly altered in both Fru and HFF groups and were closely associated with fructose and BA metabolism. In summary, excessive fructose caused gut dysbiosis and BA alterations, promoting HF-induced NAFLD. The crosstalk between Clostridium sp. and LCA species were potential targets in fructose-mediated NAFLD.

Liver-Brain Axis in Sporadic Alzheimer's Disease: Role of Ten Signature Genes in a Mouse Model.

Poor nutritional effect of junk food induces injuries to the liver and the brain but still most of the developing nations survive on these diets to compensate for the fast-paced lifestyle. The aim of the study is to infer the protein-connections behind the liver-brain axis and identify the role of these proteins in causing neurodegenerative disorders. Chronic consumption of fructose and fat-rich food works as a toxin in the body and has the ability to cause a negative metabolic shift. Recently a study was published in Annals of Internal Medicine (2019) citing the loss of vision and hearing in a 14-year-old boy whose diet was strictly restricted to fries and junk-food for almost a decade. This puts the entire body on insulin resistance and related co-morbidities and causes simultaneous damaging effects on the liver as well as the brain. This work provides insights into the liver-brain axis and explains how the liver is involved in brain related disorders. In this study, transcriptomic data related to chronic eating of junk-food was analyzed and simultaneous damage that happens in the liver and the brain was assessed at the molecular level. Transcriptomic study was taken from the GEO database and analysed to find out the genes dysregulated in both the liver and the brain during this metabolic stress. Cytoscapev3.7 was used to decipher the signalling between the liver and the brain. This connection between both is called as the liver-brain axis. The results obtained from our study indicate the role of TUBB5-HYOU1-SDF2L1-DECR1- CDH1-EGFR-SKP2-SOD1-IRAK1-FOXO1 gene signature in the decline of concurrent liver and brain health. Dysregulated levels of these genes are linked to molecular processes like cellular senescence, hypoxia, glutathione synthesis, amino acid modification, increased nitrogen content, synthesis of BCAAs, cholesterol biosynthesis, steroid hormone signalling and VEGF pathway. We strongly advocate that prolonged consumption of junk food is a major culprit in brain related disorders like Alzheimer's disease and propose that receptors for brain diseases lie outside the brain and aiming them for drug discovery and design may be beneficial in future clinical studies. This study also discusses the connection between NAFLD (non-alcoholic fatty liver disease) and sAD (sporadic Alzheimer's disease) owing to liver-brain axis.

Metabolic programming in offspring of mice fed fructose during pregnancy and lactation.

Fructose (C6H12O6), also known as levulose, is a hexose. Chronic consumption of fructose may be associated with increased intrahepatic fat concentration and the development of insulin resistance as well as an increase in the prevalence of nonalcoholic fatty liver disease and hyperlipidemia during pregnancy. Despite the existence of many studies regarding the consumption of fructose in pregnancy, its effects on fetuses have not yet been fully elucidated. Therefore, the objective of this study was to evaluate the genetic and biochemical effects in offspring (male and female) of female mice treated with fructose during pregnancy and lactation. Pairs of 60-day-old Swiss mice were used and divided into three groups; negative control and fructose, 10%/l and 20%/l doses of fructose groups. After offspring birth, the animals were divided into six groups: P1 and P2 (males and females), water; P3 and P4 (males and females) fructose 10%/l; and P5 and P6 (males and females) fructose 20%/l. At 30 days of age, the animals were euthanized for genetic and biochemical assessments. Female and male offspring from both dosage groups demonstrated genotoxicity (evaluated through comet assay) and oxidative stress (evaluated through nitrite concentration, sulfhydril content and superoxide dismutase activity) in peripheral and brain tissues. In addition, they showed nutritional and metabolic changes due to the increase in food consumption, hyperglycemia, hyperlipidemia, and metabolic syndrome. Therefore, it is suggested that high consumption of fructose by pregnant female is harmful to their offspring. Thus, it is important to carry out further studies and make pregnant women aware of excessive fructose consumption during this period.

Effect of a moderate dose of fructose in solid foods on TAG, glucose and uric acid before and after a 1-month moderate sugar-feeding period.

There are few data on the effects on TAG, glucose and uric acid of chronic consumption of a moderate dose of fructose in solid foods. Twenty-eight participants with prediabetes and/or obesity and overweight commenced the study (BMI 32·3 kg/m2, age 44·7 years, fasting glucose 5·3 (sd 0·89) mmol/l and 2-h glucose 6·6 (sd 1·8) mmol/l). Twenty-four men and women who completed the study consumed, in random order, two acute test meals of muffins sweetened with either fructose or sucrose. This was followed by 4-week chronic consumption of 42 g/d of either fructose or sucrose in low-fat muffins after which the two meal tests were repeated. The sugar type in the chronic feeding period was also randomised. Fasting TAG increased after chronic consumption of fructose by 0·31 (sd 0·37) mmol/l compared with sucrose in those participants with impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) (P = 0·004). Total cholesterol (0·33 mmol/l), LDL-cholesterol (0·24 mmol/l) and HDL-cholesterol (0·08 mmol/l) increased significantly over the 1- month feeding period with no differences between muffin types. Fasting glucose was not different after 1 month of muffin consumption. Uric acid response was not different between the two sugar types either baseline or 1 month, and there were no differences between baseline and 1 month. The increase in fasting TAG in participants with IFG/IGT suggests the need for caution in people at increased risk of type 2 diabetes.

Preventive Role of Soy Protein in Fructose Induced Metabolic Dysfunction in Rats via Inhibition of Nuclear Factor kappa B Pathway

Soy protein is an important component of soybeans that has beneficial role in improving insulin resistance. Nuclear factor kappa B (NF-κB) is a crucial pathway that has been implicated in the development of metabolic syndrome. Our study aimed to examine the protective effect of soy protein isolate - as a natural NF-κB inhibitor - and its possible mechanism of action in amelioration of inflammatory and metabolic disorders induced in male albino rats by high fructose diet (10% w/v) via using synthetic NF-κB inhibitor (IMD-0354). Rats were randomized into normal control group, soy group, NF-κB inhibitor (IMD-0354) group, high fructose group, high fructose with soy group, high fructose with NF-κB inhibitor group, high fructose with soy and NF-κB inhibitor group. Serum glucose, serum insulin, serum free fatty acids, insulin resistance (HOMA-IR), NF-κB, phosphorylated insulin receptor (pISR), carbohydrate-responsive element-binding protein (ChREBP) were determined and histopathological examination of liver tissue was performed. The concurrent administration of IMD-0354 and/or soy protein with high fructose significantly increased pISR and decreased FFAs, NF-κB, glucose, insulin, HOMA-IR, and ChREBP as well as improved the pathological conditions of the livers. The metabolic and inflammatory disorders induced by chronic consumption of fructose could be inhibited by co-administration of soy protein through regulation of NF-κB signalling pathway.

Dietary fructose and dyslipidemia: new mechanisms involving apolipoprotein CIII.

Chronic consumption of fructose and fructose-containing sugars leads to dyslipidemia. Apolipoprotein (apo) CIII is strongly associated with elevated levels of triglycerides and cardiovascular disease risk. We reviewed the effects of fructose consumption on apoCIII levels and the role of apoCIII in fructose-induced dyslipidemia. Consumption of fructose increases circulating apoCIII levels compared with glucose. The more marked effects of fructose compared with glucose on apoCIII concentrations may involve the failure of fructose consumption to stimulate insulin secretion. The increase in apoCIII levels after fructose consumption correlates with increased postprandial serum triglyceride. Further, RNA interference of apoCIII prevents fructose-induced dyslipidemia in nonhuman primates. Increases in postprandial apoCIII after fructose, but not glucose consumption, are positively associated with elevated triglycerides in large triglyceride-rich lipoproteins and increased small dense LDL levels. ApoCIII might be causal in the lipid dysregulation observed after consumption of fructose and fructose-containing sugars. Decreased consumption of fructose and fructose-containing sugars could be an effective strategy for reducing circulating apoCIII and subsequently lowering triglyceride levels.

Chronic Consumption of Fructose Induces Behavioral Alterations by Increasing Orexin and Dopamine Levels in the Rat Brain.

It has been widely described that chronic intake of fructose causes metabolic alterations which can be associated with brain function impairment. In this study, we evaluated the effects of fructose intake on the sleep–wake cycle, locomotion, and neurochemical parameters in Wistar rats. The experimental group was fed with 10% fructose in drinking water for five weeks. After treatment, metabolic indicators were quantified in blood. Electroencephalographic recordings were used to evaluate the sleep architecture and the spectral power of frequency bands. Likewise, the locomotor activity and the concentrations of orexin A and monoamines were estimated. Our results show that fructose diet significantly increased the blood levels of glucose, cholesterol, and triglycerides. Fructose modified the sleep–wake cycle of rats, increasing the waking duration and conversely decreasing the non-rapid eye movement sleep. Furthermore, these effects were accompanied by increases of the spectral power at different frequency bands. Chronic consumption of fructose caused a slight increase in the locomotor activity as well as an increase of orexin A and dopamine levels in the hypothalamus and brainstem. Specifically, immunoreactivity for orexin A was increased in the ventral tegmental area after the intake of fructose. Our study suggests that fructose induces metabolic changes and stimulates the activity of orexinergic and dopaminergic neurons, which may be responsible for alterations of the sleep–wake cycle.

Chronic Consumption of Fructose Dysregulates Genes Related to Glucose and Lipid Metabolism in Prostate Tissue

Fructose is commonly used as a taste enhancer in many processed foods. Excessive fructose consumption is highly associated with obesity and development of cancer particularly prostate cancer. This study aimed to investigate the biochemical and molecular changes in the prostate tissue of rats treated with 20% fructose for six months. A total of 18 rats weighted 200-250 g were divided into two groups, where each group consisted of 9 rats. Control group is given normal diet, while the treated group was given normal diet and 20% fructose in drinking water. After six months of treatment, both groups were sacrificed for further analysis. Body weight, blood pressure and glucose were measured. Lipid profiles were determined using quantitative colorimetric assay. Transcripts level of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), leptin (LEP), angiopoietin 1 (ANGPT1), microRNA (miR)-34a, miR-10b and miR-192 were determined using quantitative PCR, while the protein levels of 11β-HSD1 and leptin were determined using ELISA. The results showed that 20% fructose diet significantly increased blood glucose level as compared to the control (p<0.05). The transcript levels of LEP and miR-192 were significantly lower in the fructose-treated group as compared to the control (p<0.05). There was a significant linear relationship between prostate LEP and serum LDL/VLDL level as well as between the level of prostate LEP and serum total cholesterol level (p<0.05). Thus, our results showed that chronic consumption of fructose could down-regulate LEP and miR-192 expression in prostate tissue, and promote higher accumulation of fat in the tissue. Additionally, downregulation of miR-192 has been reported to be associated with the pathogenesis of prostate cancer. Thus, it can be concluded that long-term fructose diet leads to higher blood glucose level and down-regulation of LEP and miR-192 expression in prostate tissue.

Chronic Liquid Fructose, but not Glucose, Supplementation Selectively Induces Visceral Adipose Tissue Leptin Resistance and Hypertrophy in Female Sprague-Dawley Rats.

The effect of chronic supplementation with simple-sugar solutions on leptin signaling in liver, hypothalamus, and visceral white adipose tissue (vWAT) is studied, which is designed to mimic the temporal pattern of consumption by humans. Solutions of fructose or glucose are isocalorically supplemented (7 months) in female Sprague-Dawley rats consuming ad libitum rodent chow. After sacrifice, plasma and tissue samples (liver, hypothalamus, and vWAT) are collected. Zoometric parameters, plasma analytes, and the tissue expression and activity of markers of leptin signaling are determined by biochemical and molecular biological methods. The two sugars cause different types of adiposopathy. Both sugars induce increases in plasma nonesterified fatty acids, and leptin resistance in the liver and the hypothalamus. Only fructose-supplemented rats show hyperleptinemia, and increased body weight due to a hypertrophy of vWAT, with no signs of leptin-mediated lipolysis. Glucose-supplemented rats show no significant changes in these parameters but present elevated plasma adiponectin concentrations, lipolysis, and inflammatory markers in vWAT, indicating a shift to a nonexpandable adipose tissue phenotype. Chronic consumption of fructose places a greater burden on metabolic homeostasis than equivalent consumption of glucose, inducing hyperleptinemia, generalized leptin resistance, and increased body weight due to expanded, hypertrophic vWAT.

Effects of fructose consumption on postprandial TAG: an update on systematic reviews with meta-analysis.

The aim of this study was to re-examine the chronic effect (>7 d) of fructose consumption on postprandial TAG, in adolescents and adults. The research was carried out in March 2017 and used different electronic databases, such as Medline ® (Pubmed®), Embase® and Cochrane. The review considered clinical trials (parallel or crossed) that evaluated the effect of fructose consumption for a period longer than 7 d, in humans. Two investigators independently performed data extraction. The outcome was the absolute delta of TAG concentration in a 4-h postprandial period. The results were presented with delta mean difference between treatments with 95 % CI. The calculations were made based on random-effect models. Statistical heterogeneity of treatment effects between studies was assessed by Cochrane's 'Q Test' and 'I 2' inconsistency test. The meta-analysis of the twelve selected interventions (n 318) showed that fructose generated larger variation (δ) of TAG concentrations during the postprandial period, compared with other carbohydrates (mean difference: 8·02 (95 % CI 0·46, 15·58) mg/dl (0·09 (95 % CI 0·01, 0·18) mmol/l); I 2: 74 %). High heterogeneity was generated almost exclusively by one study, and its withdrawal did not alter the result. We concluded that chronic consumption of fructose (>7 d) has a negative role on postprandial TAG in healthy adolescents and adults, as well as in overweight/obese individuals, but not in diabetics.

Chronic consumption of fructose in combination with trans fatty acids but not with saturated fatty acids induces nonalcoholic steatohepatitis with fibrosis in rats.

Consumption of Western diet high in fat and fructose has been attributed to the recent epidemic of nonalcoholic fatty liver disease (NAFLD). However, the impact of specific fatty acids on the progression of NAFLD to nonalcoholic steatohepatitis (NASH) is poorly understood. In the present study, we investigated the chronic effects of consumption of fructose in combination with saturated fatty acids (SFA) or trans fatty acids (TFA) on the development of NAFLD. Male Sprague-Dawley rats were randomly assigned to six isocaloric starch/high fructose (44% of calories), high fat (39% calories) diet containing either starch-peanut oil, fructose-peanut oil, fructose-palmolein, fructose-clarified butter, fructose-coconut oil or fructose-partially hydrogenated vegetable oil and fed for 24weeks. Palmolein, clarified butter and coconut oil were used as the source of SFA whereas partially hydrogenated vegetable oil was used as the source of TFA. Peanut oil was used as the reference oil. Long-term feeding of fructose in combination with SFA or TFA induced hepatic steatosis of similar extent associated with upregulation of stearoyl CoA desaturase-1. In contrast, fructose in combination with TFA induced NASH with fibrosis as evidenced by upregulation of hepatic proinflammatory cytokine and fibrogenic gene expression, increased hepatic oxidative stress and adipocytokine imbalance. Histopathological analysis revealed the presence of NASH with fibrosis. Further, peanut oil prevented the development of NAFLD in fructose-fed rats. Fructose in combination with TFA caused NASH with fibrosis by inducing oxidative stress and inflammation, whereas, fructose in combination with SFA caused simple steatosis, suggesting that the type of fatty acid is more important for the progression of NAFLD.

Substitution of soy protein for casein prevents oxidative modification and inflammatory response induced in rats fed high fructose diet.

Fructose-rich diet is known to cause metabolic dysregulation, oxidative stress, and inflammation. We aimed to compare the effects of two dietary proteins of animal and plant origins on fructose-induced oxidative stress and inflammatory changes in liver. Wistar rats were fed either starch or fructose (60%) diet with casein or soy protein (20%) as the protein source for 8 weeks. Glucose and insulin, glycated hemoglobin and fructosamine, AOPP, and FRAP were determined in circulation. Intracellular ROS, oxidatively modified proteins (4-HNE and 3-NT adducts), adiponectin, TNF-α, IL-6 and PAI-1 mRNA expression, phosphorylation and activation of JNK and IKKβ, and NF-κB binding activity were assayed in liver. In comparison with starch fed group, fructose + casein group registered significant decline in antioxidant potential and increase in plasma glucose, insulin, and glycated proteins. Increased ROS production, 4-HNE and 3-NT modified proteins, JNK and IKKβ activation, and NF-κB binding activity were observed in them along with increased gene expression of PAI-1, IL-6, and TNF-α and decreased adiponectin expression. Substitution of soy protein for casein reduced oxidative modification and inflammatory changes in fructose-fed rats. These data suggest that soy protein but not casein can avert the adverse effects elicited by chronic consumption of fructose.

Acute intake of a high-fructose diet alters the balance of adipokine concentrations and induces neutrophil influx in the liver

The postprandial state is a period of metabolic fluxes, biosynthesis and oxidative metabolism. A considerable amount is known about the inflammatory response to the chronic consumption of fructose, but little is known about its effects in the postprandial state. The aim of the present study was to investigate the inflammatory effects of a single meal containing fructose on healthy mice. Male BALB/c and LysM-eGFP mice at 12–14 weeks were divided into three groups: fasted, control (mice fed with a sucrose-containing diet) and fructose (mice fed with a fructose-containing diet). One, 2 or 4 h postprandial, the BALB/c mice were killed, and samples were collected. LysM-eGFP mice were submitted to intravital microscopy. The fed mice showed a low-grade inflammatory response apart from dietary composition, which was characterized by increased numbers of leukocytes and high serum concentrations of pentraxin 3, leptin and resistin. TNF-α and CCL2 concentrations rose in the liver after the meal. IL-6 concentration increased and IL-10 decreased in the adipose tissue of the fed mice. Mice fed with the fructose-containing diet showed an intensification of the inflammatory response. Furthermore, the adiponectin concentration dropped, and the liver influx of neutrophils increased after fructose intake. Overall, this study showed a rapid increase in the systemic and tissue-specific immune response after a balanced meal. The study also showed an increased neutrophil influx in liver associated with an imbalance of adipokine concentrations and an increase of cytokine in the liver and adipose tissue following a fructose-containing meal.

Antigen peptide transporter 1 is involved in the development of fructose‐induced hepatic steatosis in mice

The purpose of this study is to assess whether the decrease in CD8 cells has any role in the development of non-alcoholic fatty liver disease (NAFLD). In this study, we therefore used antigen peptide transporter 1 (TAP1(-/-)) mice that cannot transport major histocompatibility complex class I antigens onto the cell surface resulting in failure of the generation of CD8 cells. Wild-type C57Bl/6J and TAP1(-/-) mice were fed with 30% fructose solution for 8 weeks. The percentage of CD4, CD8 cells in peripheral blood mononuclear cells, and liver were sorted by fluorescence-activated cell sorting in both control and fructose-treated mice. Bodyweight, histopathological changes, oil red O staining, glucose tolerance test, intraperitoneal insulin tolerance test, serum levels of triglycerides, cholesterol, aspartate aminotransferase, and alanine aminotransferase were also evaluated. Quantitative real-time polymerase chain reaction was performed to determine the expression of specific genes involved in development of fatty changes in the liver. Chronic consumption of fructose in TAP1(-/-) mice did not develop NAFLD, insulin resistance, or change in level of CD8 cells. Moreover, there was delay in relative expression levels of genes involved in development of NAFLD in fructose-treated TAP1(-/-) mice. Taken together, the data suggest that TAP1(-/-) -deficient mice displayed reduced levels of CD8 cells that have a vital role in the initiation and propagation of liver inflammation and is a casual role in the beginning of fructose-induced liver damage as well as insulin resistance in mice.

Mechanisms Underlying Fructose-Induced Oxidative Stress in the Cytosol and Mitochondria

High levels of dietary fructose are increasingly recognized as an important nutritional factor in the development of nonalcoholic fatty liver disease and intestinal inflammation in both humans and animal models. The signals linking excessive fructose intake on one hand and the onset of these pathologies are not known. We have employed genetically encoded biosensors sensitive to changes in superoxide anion (O2- ) or hydrogen peroxide (H2O2) concentrations to test the hypothesis that fructose metabolism increases the production of reactive oxygen species (ROS) in hepatocytes or intestinal cells. The data indicate that acute treatment with physiological concentrations of fructose (1 - 10 mM) significantly increased the formation of mitochondrial O2- as well as mitochondrial and cytosolic H2O2. The xanthine oxidase inhibitor, allopurinol, inhibited fructose-induced increases in cytosolic H2O2, but was unaffected by apocynin, a NADPH oxidase inhibitor. These data are consistent with the well known effects of acute fructose treatment to reduce ATP levels and stimulate the breakdown of purines. Fructose-induced ROS production in the mitochondria was not altered by allopurinol treatment, whereas apocynin strongly suppressed mitochondrial derived ROS. Fructose administration transiently increased ROS formation in all mitochondria regardless of the subcellular localization and this was paralleled by a sustained rise in mitochondrial membrane potential and an increase in pyridine nucleotide fluorescence. The activation of mitochondrial metabolism was followed by large amplitude O2- bursts in a subset of mitochondria. The addition of mitochondrial respiration inhibitors blocked the effects of fructose on mitochondrial, but not cytosolic ROS production. Taken together, these data indicate that fructose treatment stimulates mitochondrial metabolism leading to an increase in ROS production through an apocynin sensitive pathway. Finally, we show that chronic consumption of fructose results in markedly higher baseline levels of mitochondrial ROS in hepatocytes.