Fructose Supplementation Research Articles

Oxidative stress and metabolic parameters are differently affected by fructose when rats were kept sedentary or underwent swimming exercise.

The current study evaluated whether fructose supplementation affects oxidative stress and metabolic parameters in the liver and gastrocnemius muscle of rats subjected to swimming exercise. Male adult Wistar rats received a fructose solution (10%) or water during 1 h before exercise and during the rest interval by the intragastric route. The swimming protocol consisted of 6 days: each day, rats underwent 3 sessions of 17 min each, with a load of 5% of body mass, and rest intervals of 3 min. Fructose supplementation changed metabolic and oxidative parameters in the liver and gastrocnemius muscle of sedentary rats. Swimming exercise counteracted the increase of triglyceride levels in plasma and liver induced by fructose supplementation. It also reduced thiobarbituric acid reactive species levels in the liver, and catalase and superoxide dismutase activities in the gastrocnemius muscle of supplemented rats. However, fructose supplementation worsened metabolic (hepatic triglyceride levels) and oxidative parameters (thiobarbituric acid reactive species levels) in the liver and gastrocnemius of exercised rats. This study demonstrates that oxidative stress and metabolic parameters were differently affected by fructose supplementation when rats were kept sedentary or underwent swimming exercise. The present results indicate the need of a new insight of the role of fructose supplementation during physical exercise.

Fructose-induced hypertriglyceridemia in rhesus macaques is attenuated with fish oil or ApoC3 RNA interference

Dyslipidemia and insulin resistance are significant adverse outcomes of consuming high-sugar diets. Conversely, dietary fish oil (FO) reduces plasma lipids. Diet-induced dyslipidemia in a rhesus model better approximates the pathophysiology of human metabolic syndrome (MetS) than rodent models. Here, we investigated relationships between metabolic parameters and hypertriglyceridemia in rhesus macaques consuming a high-fructose diet (n = 59) and determined the effects of FO supplementation or RNA interference (RNAi) on plasma ApoC3 and triglyceride (TG) concentrations. Fructose supplementation increased body weight, fasting insulin, leptin, TGs, and large VLDL particles and reduced adiponectin concentrations (all P < 0.001). In multiple regression analyses, increased plasma ApoC3 was the most consistent and significant variable related to diet-induced hypertriglyceridemia. FO supplementation, which attenuated increases of plasma TG and ApoC3 concentrations, reversed fructose-induced shifts of lipoprotein particle size toward IDL and VLDL, a likely mechanism contributing to beneficial metabolic effects, and reduced hepatic expression of genes regulated by the SREBP pathway, particularly acetyl-CoA carboxylase. Furthermore, RNAi-mediated ApoC3 inhibition lowered plasma TG concentrations in animals with diet-induced hypertriglyceridemia. In summary, ApoC3 is an important independent correlate of TG-rich lipoprotein concentrations in rhesus macaques consuming a high-fructose diet. ApoC3 is a promising therapeutic target for hypertriglyceridemia in patients with MetS and diabetes.

Cross Talk between Apical Periodontitis and Metabolic Disorders: Experimental Evidence on the Role of Intestinal Adipokines and Akkermansia muciniphila

IntroductionInfection and dysbiosis present a close relationship with metabolic diseases although the influence of apical periodontitis (AP) in this context needs further investigation. This study evaluated the influence of AP in a rat model of metabolic syndrome induced by 10% fructose supplementation. MethodsMale Wistar rats were used. Animals that received a high-fructose diet (HFD, n = 30) or filtered water (control, n = 30) were subdivided into the following groups:(1) without induction of AP (no AP, n = 10 each),(2) with AP induction 2 weeks before euthanasia (AP 14 days, n = 10 each), and(3) with AP induction 4 weeks before euthanasia (AP 28 days, n = 10 each). ResultsHFD triggered metabolic syndrome, as indicated by the induction of overweight and hyperglycemia, besides polydipsia, regardless of the AP induction. Serum or intestinal tumor necrosis factor, interleukin 1 beta, and interleukin 6 levels were undetectable, regardless of the experimental group. Serum leptin and adiponectin levels were significantly elevated in the HFD group without AP induction. The intestinal levels of leptin were significantly increased in the groups with 28 days of AP induction despite HFD. A significant elevation of liver glutathione levels was observed in animals submitted to HFD and AP for 14 days. AP induction (14 or 28 days) led to pulp and periapical tissue inflammation without any influence of HFD. Either HFD or AP induction led to dysbiosis, as indicated by a significant reduction of fecal A. muciniphila expression. ConclusionsWe provide novel evidence that AP can have systemic impacts on metabolic disorders, likely by modulating intestinal metabolism and microbiota.

Repercussions of low fructose-drinking water in male rats.

Fructose consumption has increased worldwide, and it has been associated with the development of metabolic diseases such as insulin resistance (IR) and steatosis. The aim was to evaluate if lower fructose concentrations may cause pancreatic structural abnormalities, leading to a glucose intolerance without steatosis in male rats. Young male rats orally received 7% fructose solution for 12 weeks. Body weight, food, water, and energy intake were measured. An oral glucose tolerance test (OGTT) was performed. After final experimental period, all rats were anaesthetized and killed. Blood samples were collected for biochemical analyses and organs (liver and pancreas) were processed for morphological analyses. Fructose consumption was not associated with lipid accumulation in liver. However, fructose administration was associated with an increased area under curve from OGTT and an increased percentage of insulin-positive cells, high beta cell mass and reduced pancreatic islet area. Fructose supplementation (7%) did not cause steatosis, but it led to abnormal morphology and function of pancreatic islet cells, contributing for glucose intolerance development. Our findings demonstrate that even low fructose concentrations may cause deleterious effects in animals.

Temporal dynamics of liver mitochondrial protein acetylation and succinylation and metabolites due to high fat diet and/or excess glucose or fructose.

Dietary macronutrient composition alters metabolism through several mechanisms, including post-translational modification (PTM) of proteins. To connect diet and molecular changes, here we performed short- and long-term feeding of mice with standard chow diet (SCD) and high-fat diet (HFD), with or without glucose or fructose supplementation, and quantified liver metabolites, 861 proteins, and 1,815 protein level-corrected mitochondrial acetylation and succinylation sites. Nearly half the acylation sites were altered by at least one diet; nutrient-specific changes in protein acylation sometimes encompass entire pathways. Although acetyl-CoA is an intermediate in both sugar and fat metabolism, acetyl-CoA had a dichotomous fate depending on its source; chronic feeding of dietary sugars induced protein hyperacetylation, whereas the same duration of HFD did not. Instead, HFD resulted in citrate accumulation, anaplerotic metabolism of amino acids, and protein hypo-succinylation. Together, our results demonstrate novel connections between dietary macronutrients, protein post-translational modifications, and regulation of fuel selection in liver.

Deep Ocean Minerals Minimize Eccentric Exercise-Induced Inflammatory Response of Rat Skeletal Muscle.

Background: We have previously shown an accelerated recovery from muscle fatigue in men challenged by prolonged exercise after oral deep ocean minerals (DOM) supplementation. Here, we hypothesized a decrease in eccentric exercise-induced muscle inflammation in rats regularly consuming DOM-containing drinks (hardness 600 mg/L and fructose 11%).Methods: Forty-seven male Sprague Dawley rats were randomized into 4 groups: Control (C, N = 12), Fructose (F, N = 12), Fructose+Exercise (FE, N = 12), and Fructose+Exercise+DOM (FED, N = 11). Since fructose is a commonly used ingredient in beverages, 11% of fructose was added as a vehicle of the study. Soleus muscles of rats were analyzed 24 h after an acute bout of downhill running following 9 weeks of DOM supplementation.Results: Leukocyte infiltration and TNF-α mRNA of muscle in the FE group were 5 times and 4 times greater the F group, respectively, (P < 0.05). Both markers in the FED group were significantly lower than those in the FE group (P < 0.05). IL-10 mRNA of muscle in the F group was >eight fold greater than the C group (P < 0.05). The reduced glutathione (GSH) of muscle in the F group was 34% lower than that in the C group (P < 0.05). However, GSH levels were similar for the C and FED groups.Conclusion: Prolonged fructose supplementation modulates inflammatory balance of rat skeletal muscle. The results of the study suggest that DOM can minimize eccentric exercise-induced inflammatory cytokine responses in rat skeletal muscle.

Lack of liver steatosis in germ-free mice following hypercaloric diets.

Experimental liver steatosis induced by overfeeding is associated with enhanced gut permeability and endotoxin translocation to the liver. We examined the role of the gut microbiota for steatosis formation by performing the feeding experiments in mice raised under conventional and germ-free (GF) housing. Adult wild-type and GF mice were fed a Western-style diet (WSD) or a control diet (CD), the latter combined with liquid fructose supplementation (F) or not, for 8 weeks. Markers of liver steatosis and gut permeability were measured after intervention. Mice fed a WSD increased body weight compared to those fed a CD (p < 0.01) under conventional, but not under GF conditions. Increased liver weight, liver-to-body-weight ratio and hepatic triglycerides observed in both the WSD and the CD + F groups, when compared with the CD group, were not apparent under GF conditions, whereas elevated plasma triglycerides were visible (p < 0.05). Wild-type mice fed a WSD or a CD + F, respectively, had thinner adherent mucus layer compared to those fed a CD (p < 0.01), whereas GF mice had always a thin mucus layer independently of the diet. GF mice fed a CD showed increased plasma levels of FITC-dextran 4000 (1.9-fold, p < 0.05) and intestinal fatty acid-binding protein-2 (2.4-fold, p < 0.05) compared with wild-type mice. GF housing results in an impaired weight gain and a lack of steatosis following a WSD. Also the fructose-induced steatosis, which is unrelated to body weight changes, is absent in GF mice. Thus, diet-induced experimental liver steatosis depends in multiple ways on intestinal bacteria.

High Fructose Intake During Pregnancy in Rats Influences the Maternal Microbiome and Gut Development in the Offspring.

Studies in pregnant women indicate the maternal microbiome changes during pregnancy so as to benefit the mother and fetus. In contrast, disruption of the maternal microbiota around birth can compromise normal bacterial colonisation of the infant’s gastrointestinal tract. This may then inhibit development of the gut so as to increase susceptibility to inflammation and reduce barrier function. The impact of modulating fructose intake on the maternal microbiome through pregnancy is unknown, therefore we examined the effect of fructose supplementation on the maternal microbiome together with the immediate and next generation effects in the offspring. Wistar rat dams were divided into control and fructose fed groups that received 10% fructose in their drinking water from 8 weeks of age and throughout pregnancy (10–13 weeks). Maternal fecal and blood samples were collected pre-mating (9 weeks) and during early (gestational day 4–7) and late pregnancy (gestational day 19–21). We show supplementation of the maternal diet with fructose appears to significantly modulate the maternal microbiome, with a significant reduction in Lactobacillus and Bacteroides. In offspring maintained on this diet up to pregnancy and term there was a reduction in gene expression of markers of gut barrier function that could adversely affect its function. An exacerbated insulin response to pregnancy, reduced birth weight, but increased fat mass was also observed in these offspring. In conclusion dietary supplementation with fructose modulates the maternal microbiome in ways that could adversely affect fetal growth and later gut development.

Detrimental Effects of Aging, Ovariectomy and Weight Gain on Left Ventricular Structure and Function: A Potential Preclinical Model of Early Stage HFpEF

The incidence of heart failure with preserved ejection fraction (HFpEF) continues to increase and little is known about its pathophysiology. Two‐thirds of HFpEF patients are senile women and risk factors include hypertension and metabolic syndrome. Currently, no drugs are effective for HFpEF treatment and the development of animal models would assist in novel therapy evaluation. We implemented a rodent female animal model of aging, estrogen depletion and weight gain to evaluate the role of these factors in altering cardiac structure/function. Female, 18 month old, Fischer F344 rats were allocated into an aging (A) group, aging + ovariectomy (O) and aging + ovariectomy and 10% fructose (OF) in drinking water (n=8–13/group). For comparison purposes a young (3 month old, n=8) cohort of female rats was included. Left ventricular (LV) structure/function was monitored monthly by echocardiography. At 22 months of age, animals were anesthetized and LV function evaluated using a Millar conductance catheter. Histological measures of chamber morphometry, inflammation and collagen density (fibrosis) were also obtained. OF animals significantly increased body weight vs. A and O. While echocardiography did not detect major alterations in cardiac endpoints, intraventricular pressure‐volume loop analysis evidenced significant (p&lt;0.05) decreases in stroke volume (19% O and 27% for OF vs. A), stroke work (27 O and 31% OF vs. A), cardiac output (43 O and 44% OF vs. A) and increases in Tau (30–35% in A, O and OF vs. young) and LV end‐diastolic pressure volume relationship slope (i.e. stiffness) with ovariectomy in the presence of preserved ejection fraction for all groups. Histomorphometry did not detect changes in chamber dimensions. However, histological analysis indicated progressively increasing levels of inflammatory infiltration, perivascular and interstitial fibrosis with ovariectomy and with fructose supplementation in particular, in the subendocardium (see figure). In conclusion, in the setting of aging, ovariectomy (which depletes estrogens), further deteriorates myocardial microstructure which may facilitate the loss of diastolic and global functional indices in the apparent presence of preserved ejection fraction. This model may serve to understand the role that estrogen depletion and weight gain may have in the development of HFpEF.Support or Funding InformationDoD 150090 to FVThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Fructose-Enhanced Antimicrobial Activity of Silver Nanoparticle-Embedded Polymersome Nanocarriers.

In recent years, an increasing body of research has indicated that the antimicrobial activity of certain antibiotic drugs can be enhanced by the addition of specific metabolites. This study aimed to incorporate these findings into polymersomes (novel polymer-based nanoscale drug delivery vehicles) which can be loaded with various therapeutic molecules and nanoparticles. Polymersome technology has shown promising results in treating antibiotic-resistant infections by co-encapsulating the antibiotic methicillin with silver nanoparticles. Here, silver nanoparticle-embedded polymersomes (AgPs) were synthesized in a similar fashion with gentamicin replacing methicillin as the antibiotic agent and supplemented with fructose to promote efficacy. Two clinically-isolated strains of methicillin-resistant Staphylococcus aureus (MRSA) (ATCC #43300 and ATCC #25923) were cultured and treated with the new AgP formulations, with the former strain being susceptible to gentamicin and the latter strain being resistant to gentamicin. The treatment of the non-resistant strain yielded promising results with the polymersomes without fructose supplementation inducing a maximal growth rate reduction of up to 40% and an increase in lag time of up to 141% relative to the untreated control. Impressively, the fructose-loaded polymersomes completely eliminated the bacterial growth over the observed time period at the higher doses and outperformed the no-fructose treatment at all concentrations. However, despite significantly reducing bacterial growth, the treatment of the gentamicin-resistant strain did not seem to be enhanced by the addition of fructose. Lastly, the present study demonstrated that the presence of fructose in the polymersomes seemed to slightly ameliorate the cytotoxic effect of the treatment on human dermal fibroblasts (a model mammalian cell). In addition to developing and testing a new polymersome formulation with fructose resulting in increased efficacy, the results of this study also demonstrated the variability inherent to developing novel antimicrobial treatments for different bacterial strains.

Impairment of Novel Object Recognition Memory and Brain Insulin Signaling in Fructose- but Not Glucose-Drinking Female Rats.

Excessive sugar intake has been related to cognitive alterations, but it remains unclear whether these effects are related exclusively to increased energy intake, and the molecular mechanisms involved are not fully understood. We supplemented Sprague-Dawley female rats with 10% w/v fructose in drinking water or with isocaloric glucose solution for 7months. Cognitive function was assessed through the Morris water maze (MWM) and the novel object recognition (NOR) tests. Plasma parameters and protein/mRNA expression in the frontal cortex and hippocampus were determined. Results showed that only fructose-supplemented rats displayed postprandial and fasting hypertriglyceridemia (1.4 and 1.9-fold, p < 0.05) and a significant reduction in the discrimination index in the NOR test, whereas the results of the MWM test showed no differences between groups. Fructose-drinking rats displayed an abnormal glucose tolerance test and impaired insulin signaling in the frontal cortex, as revealed by significant reductions in insulin receptor substrate-2 protein levels (0.77-fold, p < 0.05) and Akt phosphorylation (0.72-fold, p < 0.05), and increased insulin-degrading enzyme levels (1.86-fold, p < 0.001). Fructose supplementation reduced the expression of antioxidant enzymes and altered the amount of proteins involved in mitochondrial fusion/fission in the frontal cortex. In conclusion, cognitive deficits induced by chronic liquid fructose consumption are not exclusively related to increased caloric intake and are correlated with hypertriglyceridemia, impaired insulin signaling, increased oxidative stress and altered mitochondrial dynamics, especially in the frontal cortex.

Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling.

Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for developing obesity, insulin resistance, and fatty liver disease. Here we have dissected mechanisms underlying this association using mice fed either chow or HFD with or without fructose- or glucose-supplemented water. In chow-fed mice, there was no major physiological difference between fructose and glucose supplementation. On the other hand, mice on HFD supplemented with fructose developed more pronounced obesity, glucose intolerance, and hepatomegaly as compared to glucose-supplemented HFD mice, despite similar caloric intake. Fructose and glucose supplementation also had distinct effects on expression of the lipogenic transcription factors ChREBP and SREBP1c. While both sugars increased ChREBP-β, fructose supplementation uniquely increased SREBP1c and downstream fatty acid synthesis genes, resulting in reduced liver insulin signaling. In contrast, glucose enhanced total ChREBP expression and triglyceride synthesis but was associated with improved hepatic insulin signaling. Metabolomic and RNA sequence analysis confirmed dichotomous effects of fructose and glucose supplementation on liver metabolism in spite of inducing similar hepatic lipid accumulation. Ketohexokinase, the first enzyme of fructose metabolism, was increased in fructose-fed mice and in obese humans with steatohepatitis. Knockdown of ketohexokinase in liver improved hepatic steatosis and glucose tolerance in fructose-supplemented mice. Thus, fructose is a component of dietary sugar that is distinctively associated with poor metabolic outcomes, whereas increased glucose intake may be protective.

The Addition of Liquid Fructose to a Western-Type Diet in LDL-R-/- Mice Induces Liver Inflammation and Fibrogenesis Markers without Disrupting Insulin Receptor Signalling after an Insulin Challenge.

A high consumption of fat and simple sugars, especially fructose, has been related to the development of insulin resistance, but the mechanisms involved in the effects of these nutrients are not fully understood. This study investigates the effects of a Western-type diet and liquid fructose supplementation, alone and combined, on insulin signalling and inflammation in low-density lipoprotein (LDL) receptor-deficient mice (LDL-R−/−). LDL-R−/− mice were fed chow or Western diet ±15% fructose solution for 12 weeks. Plasma glucose and insulin, and the expression of genes related to inflammation in the liver and visceral white adipose tissue (vWAT), were analysed. V-akt murine thymoma viral oncogene homolog-2 (Akt) activation was measured in the liver of the mice after a single injection of saline or insulin. None of the dietary interventions caused inflammation in vWAT, whereas the Western diet induced hepatic inflammation, which was further enhanced by liquid fructose, leading also to a significant increase in fibrogenesis markers. However, there was no change in plasma glucose or insulin, or insulin-induced Akt phosphorylation. In conclusion, hepatic inflammation and fibrogenesis markers induced by a Western diet supplemented with liquid fructose in LDL-R−/− mice are not associated with a significant impairment of hepatic insulin signalling.

The Effect of Short-Term Dietary Fructose Supplementation on Gastric Emptying Rate and Gastrointestinal Hormone Responses in Healthy Men.

This study aimed to examine gastric emptying rate and gastrointestinal hormone responses to fructose and glucose ingestion following 3 days of dietary fructose supplementation. Using the 13C-breath test method, gastric emptying rates of equicaloric fructose and glucose solutions were measured in 10 healthy men with prior fructose supplementation (fructose supplement, FS; glucose supplement, GS) and without prior fructose supplementation (fructose control, FC; glucose control, GC). In addition, circulating concentrations of acylated ghrelin (GHR), glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and insulin were determined, as well as leptin, lactate, and triglycerides. Increased dietary fructose ingestion resulted in accelerated gastric emptying rate of a fructose solution but not a glucose solution. No differences in GIP, GLP-1, or insulin incremental area under curve (iAUC) were found between control and supplement trials for either fructose or glucose ingestion. However, a trend for lower ghrelin iAUC was observed for FS compared to FC. In addition, a trend of lower GHR concentration was observed at 45 min for FS compared to FC and GHR concentration for GS was greater than GC at 10 min. The accelerated gastric emptying rate of fructose following short-term supplementation with fructose may be partially explained by subtle changes in delayed postprandial ghrelin suppression.

Metabolic Syndrome and Hypertension Resulting from Fructose Enriched Diet in Wistar Rats.

Increased sugar consumption, especially fructose, is strongly related to the development of type 2 diabetes (T2D) and metabolic syndrome. The aim of this study was to evaluate long term effects of fructose supplementation on Wistar rats. Three-week-old male rats were randomly divided into 2 groups: control (C; n = 14) and fructose fed (FF; n = 18), with a fructose enriched drink (20–25% w/v fructose in water) for 21 weeks. Systolic blood pressure, fasting glycemia, and bodyweight were regularly measured. Glucose tolerance was evaluated three times using an oral glucose tolerance test. Insulin levels were measured concomitantly and insulin resistance markers were evaluated (HOMA 2-IR, Insulin Sensitivity Index for glycemia (ISI-gly)). Lipids profile was evaluated on plasma. This fructose supplementation resulted in the early induction of hypertension without renal failure (stable theoretical creatinine clearance) and in the progressive development of fasting hyperglycemia and insulin resistance (higher HOMA 2-IR, lower ISI-gly) without modification of glucose tolerance. FF rats presented dyslipidemia (higher plasma triglycerides) and early sign of liver malfunction (higher liver weight). Although abdominal fat weight was increased in FF rats, no significant overweight was found. In Wistar rats, 21 weeks of fructose supplementation induced a metabolic syndrome (hypertension, insulin resistance, and dyslipidemia) but not T2D.

Type of supplemented simple sugar, not merely calorie intake, determines adverse effects on metabolism and aortic function in female rats.

This is the first study comparing the effects of glucose and fructose consumption on metabolic factors and aortic function in female rats. Our results show that, although total caloric consumption was higher in glucose-supplemented rats, fructose ingestion had a greater impact in inducing metabolic and aortic dysfunction.

Liquid fructose in Western-diet-fed mice impairs liver insulin signaling and causes cholesterol and triglyceride loading without changing calorie intake and body weight

Background/objectivesLiquid fructose associates with prevalence of type 2 diabetes mellitus and obesity. Intervention studies suggest that metabolically unfit individuals are more responsive than healthy individuals to liquid fructose. We determined whether mice consuming an obesogenic Western diet were more responsive than chow-fed mice to the alterations induced by liquid fructose supplementation (LFS). MethodsC57BL/6N mice were fed chow or Western diet±ad libitum 15% fructose solution for 12 weeks. Food and liquid intake and body weight were monitored. Plasma analytes and liver lipids, histology and the expression of genes related to lipid handling, endoplasmic reticulum stress, inflammation and insulin signaling were analyzed. ResultsWestern diet increased energy intake, visceral adipose tissue (vWAT), body weight, plasma and liver triglycerides and cholesterol, and inflammatory markers in vWAT vs. chow-fed mice. LFS did not change energy intake, vWAT or body weight. LFS significantly increased plasma and liver triglycerides and cholesterol levels only in Western-diet-fed mice. These changes associated with a potentiation of the increased liver expression of PPARγ and CD36 that was observed in Western-fed mice and related to the increased liver mTOR phosphorylation induced by LFS. Furthermore, LFS in Western-diet-fed mice induced the largest reduction in liver IRS2 protein and a significant decrease in whole-body insulin sensitivity. ConclusionsLFS in mice, in a background of an unhealthy diet that already induces fatty liver visceral fat accretion and obesity, increases liver lipid burden, hinders hepatic insulin signaling and diminishes whole-body insulin sensitivity without changing energy intake.

Liquid fructose supplementation in western diet-fed C57BL/6N mice causes liver cholesterol loading without changing calorie intake and body weight

Liquid fructose supplementation in western diet-fed C57BL/6N mice causes liver cholesterol loading without changing calorie intake and body weight

Fructose, but not glucose, impairs insulin signaling in the three major insulin-sensitive tissues.

Human studies support the relationship between high intake of fructose-sweetened beverages and type 2 diabetes, but there is a debate on whether this effect is fructose-specific or it is merely associated to an excessive caloric intake. Here we investigate the effects of 2 months’ supplementation to female rats of equicaloric 10% w/v fructose or glucose solutions on insulin sensitivity in target tissues. Fructose supplementation caused hepatic deposition of triglycerides and changed the fatty acid profile of this fraction, with an increase in monounsaturated and a decrease in polyunsaturated species, but did not cause inflammation and oxidative stress. Fructose but not glucose-supplemented rats displayed an abnormal glucose tolerance test, and did not show increased phosphorylation of V-akt murine thymoma viral oncogene homolog-2 (Akt) in white adipose tissue and liver after insulin administration. In skeletal muscle, phosphorylation of Akt and of Akt substrate of 160 kDA (AS160) was not impaired but the expression of the glucose transporter type 4 (GLUT4) in the plasma membrane was reduced only in fructose-fed rats. In conclusion, fructose but not glucose supplementation causes fatty liver without inflammation and oxidative stress and impairs insulin signaling in the three major insulin-responsive tissues independently from the increase in energy intake.

Enhanced Dietary Fructose Rapidly Induces Salt‐Sensitive Hypertension in Rats

Fructose consumption is associated with increased sodium reabsorption, increased formation of reactive oxygen species, and the development of hypertension. In normal rats, 20% dietary fructose supplementation induces hypertension within 8–12 weeks. We hypothesized a diet combining 20% fructose supplemented with high salt (4% NaCl) would induce abnormal sodium retention, increased oxidative stress, and accelerate the development of elevated blood pressure. Rats weighing 200–225 g were pre‐trained for 2 weeks for non‐invasive tail cuff blood pressure measurements and then placed in metabolic caging. Rats were pair‐fed for 2 weeks with one of 4 different diets: 1) control group (0.4% NaCl), 2) high salt chow group (4% NaCl), 3) 20% fructose group (in the drinking water), and 4) 20% fructose plus high salt group (n's = 9,5,9,18). Blood pressure, urinary sodium excretion and cumulative sodium balance were measured over 2 weeks and urinary 8‐Isoprostane excretion, as a marker for reactive oxygen species, during the final two days. High salt chow replaced normal chow at the beginning of the second week. By the end of the protocol, systolic blood pressure was unchanged in control group (121±2 to 122±2 mmHg) as well as the high salt group (122±2 to 122±1 mmHg). 20% fructose alone had no effect on blood pressure over the 2 weeks (121±1 to 125±1 mmHg). However, blood pressure significantly increased in the 20% fructose plus high salt group (125 to 140 mmHg p&lt;0.001). The increased blood pressure was concomitant with increased positive cumulative sodium balance. During the final week mean urinary sodium excretion in the high salt and 20% fructose plus high salt groups were 5–6 fold higher than normal salt controls (p&lt;0.001): 1.13±0.07, 7.67±0.31, 1.20±0.10, 5.33±0.21 μmol/24 hrs, respectively. Despite similar consumption, urinary sodium excretion in the 20% fructose plus high salt group was significantly lower than the high salt group (p&lt;0.0001). Urinary 8‐Isoprostane excretion was significantly higher in the high salt, 20% fructose, and 20% fructose plus high salt groups compared to control: 16.4±1.3, 29.5±2.5, 32.2±3.9, 31.2±2.5 ng/24 hrs, (p&lt;0.001). Our results suggests enhanced fructose and salt consumption increases sodium retention and oxidative stress. High salt can induce elevations in blood pressure in 20% fructose‐fed rats within just one week. Increased blood pressure appears to associate with increased sodium retention and positive cumulative sodium balance. Overall, fructose combined with high salt in the diet contributes to the accelerated development of salt‐sensitive hypertension.Support or Funding InformationNational Institutes of Health Grant 5P01HL090550‐05