Excessive Fructose Consumption Research Articles

Allopurinol ameliorates high fructose diet induced hepatic steatosis in diabetic rats through modulation of lipid metabolism, inflammation, and ER stress pathway

Excess fructose consumption contributes to development obesity, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD). Uric acid (UA), a metabolite of fructose metabolism, may have a direct role in development of NAFLD, with unclear mechanism. This study aimed to evaluate role of fructose and UA in NAFLD and explore mechanisms of allopurinol (Allo, a UA lowering medication) on NAFLD in Otsuka Long-Evans Tokushima Fatty (OLETF) rats fed a high fructose diet (HFrD), with Long-Evans Tokushima Otsuka (LETO) rats used as a control. There were six groups: LETO, LETO-Allo, OLETF, OLETF-Allo, OLETF-HFrD, and OLETF-HFrD-Allo. HFrD significantly increased body weight, epididymal fat weight, and serum concentrations of UA, cholesterol, triglyceride, HbA1c, hepatic enzymes, HOMA-IR, fasting insulin, and two hour-glucose after intraperitoneal glucose tolerance tests, as well as NAFLD activity score of liver, compared to the OLETF group. Allopurinol treatment significantly reduced hepatic steatosis, epididymal fat, serum UA, HOMA-IR, hepatic enzyme levels, and cholesterol in the OLETF-HFrD-Allo group. Additionally, allopurinol significantly downregulated expression of lipogenic genes, upregulated lipid oxidation genes, downregulated hepatic pro-inflammatory cytokine genes, and decreased ER-stress induced protein expression, in comparison with the OLETF-HFrD group. In conclusion, allopurinol ameliorates HFrD-induced hepatic steatosis through modulation of hepatic lipid metabolism, inflammation, and ER stress pathway. UA may have a direct role in development of fructose-induced hepatic steatosis, and allopurinol could be a candidate for prevention or treatment of NAFLD.

The Role of Fructose in Non-Alcoholic Steatohepatitis: Old Relationship and New Insights.

Non-alcoholic fatty liver disease (NAFLD) represents the result of hepatic fat overload not due to alcohol consumption and potentially evolving to advanced fibrosis, cirrhosis, and hepatocellular carcinoma. Fructose is a naturally occurring simple sugar widely used in food industry linked to glucose to form sucrose, largely contained in hypercaloric food and beverages. An increasing amount of evidence in scientific literature highlighted a detrimental effect of dietary fructose consumption on metabolic disorders such as insulin resistance, obesity, hepatic steatosis, and NAFLD-related fibrosis as well. An excessive fructose consumption has been associated with NAFLD development and progression to more clinically severe phenotypes by exerting various toxic effects, including increased fatty acid production, oxidative stress, and worsening insulin resistance. Furthermore, some studies in this context demonstrated even a crucial role in liver cancer progression. Despite this compelling evidence, the molecular mechanisms by which fructose elicits those effects on liver metabolism remain unclear. Emerging data suggest that dietary fructose may directly alter the expression of genes involved in lipid metabolism, including those that increase hepatic fat accumulation or reduce hepatic fat removal. This review aimed to summarize the current understanding of fructose metabolism on NAFLD pathogenesis and progression.

Consumption of vitamin A-deficient diet elevates endoplasmic reticulum stress marker and suppresses high fructose-induced orexigenic gene expression in the brain of male Wistar rats

ABSTRACT Vitamin A deficiency and excessive fructose consumption are known to cause functional impairment of various vital organs including the brain in the mammalian system. However, the underlying pathways and molecular mechanisms are not fully understood. Objective Here, we assessed the impact of vitamin A deficiency (both alone and in combination with fructose) on the retinol status, phospholipids fatty acid composition and pathways associated with the endoplasmic reticulum (ER) stress and energy homeostasis of the brain. For this purpose, weanling male Wistar rats were divided into four groups consisting of 8 rats each, except 16 for the second group and they received one of the following diets; control, vitamin A-deficient (VAD), high fructose (HFr) and HFr with VAD for 16 weeks, except half of the VAD diet-fed rats, were shifted to HFr diet, after 8 weeks period. Results The retinol content of the whole brain remained comparable across the groups, despite a significant reduction in the plasma at the end of VAD diet feeding. However, it suppressed the HFr-induced neuropeptide Y and agouti-related peptide, while rescuing the leptin receptor mRNA. Among ER stress markers, CCAAT/Enhancer-binding protein homologues protein levels were elevated significantly in the VAD diet-fed group. Further, the long-chain polyunsaturated fatty acid levels showed an increase in the brain phospholipids across the experimental groups, compared to that of the control. Conclusion Vitamin A deficiency causes ER stress in the brain, and retinol seems to play a regulatory role in the fructose-mediated transcriptional regulation of the genes involved in energy homeostasis.

Fructose Removal from the Diet Reverses Inflammation, Mitochondrial Dysfunction, and Oxidative Stress in Hippocampus.

Young age is often characterized by high consumption of processed foods and fruit juices rich in fructose, which, besides inducing a tendency to become overweight, can promote alterations in brain function. The aim of this study was therefore to (a) clarify brain effects resulting from fructose consumption in juvenile age, a critical phase for brain development, and (b) verify whether these alterations can be rescued after removing fructose from the diet. Young rats were fed a fructose-rich or control diet for 3 weeks. Fructose-fed rats were then fed a control diet for a further 3 weeks. We evaluated mitochondrial bioenergetics by high-resolution respirometry in the hippocampus, a brain area that is critically involved in learning and memory. Glucose transporter-5, fructose and uric acid levels, oxidative status, and inflammatory and synaptic markers were investigated by Western blotting and spectrophotometric or enzyme-linked immunosorbent assays. A short-term fructose-rich diet induced mitochondrial dysfunction and oxidative stress, associated with an increased concentration of inflammatory markers and decreased Neurofilament-M and post-synaptic density protein 95. These alterations, except for increases in haptoglobin and nitrotyrosine, were recovered by returning to a control diet. Overall, our results point to the dangerous effects of excessive consumption of fructose in young age but also highlight the effect of partial recovery by switching back to a control diet.

Fructose and Non-Alcoholic Steatohepatitis

Background: The excessive consumption of free sugars is mainly responsible for the high prevalence of obesity and metabolic syndrome in industrialized countries. More and more studies indicate that fructose is involved in the pathophysiology and also in the degree of disease of non-alcoholic fatty liver disease (NAFLD). In epidemiologic studies, energy-adjusted higher fructose consumption correlates with NAFLD in overweight adults. In addition to glucose, fructose, as an equivalent component of conventional household sugar, appears to have negative metabolic effects in particular due to its exclusive hepatic metabolism. Liver-related mortality is strictly associated with the degree of fibrosis, whereas the most common cause of death in patients suffering from NAFLD and non-alcoholic steatohepatitis (NASH) are still cardiovascular diseases. In this review article, we have summarized the current state of knowledge regarding a relationship between fructose consumption, liver fibrosis and life expectancy in NASH. Method: Selective literature search in PubMed using the keywords ‘non-alcoholic fatty liver’, ‘fructose’, and ‘fibrosis’ was conducted. Results: The rate of overweight and obesity is significantly higher in both, adult and pediatric NASH patients. The consumption of free sugars is currently three times the maximum recommended amount of 10% of the energy intake. The current literature shows weight gain, negative effects on fat and carbohydrate metabolism and NASH with hypercaloric intake of fructose. Conclusions: Excessive fructose consumption is associated with negative health consequences. Whether this is due to an excess of energy or the particular metabolism of fructose remains open with the current study situation. The urgently needed reduction in sugar consumption could be achieved through a combination of binding nutritional policy measures including taxation of sugary soft drinks. Previous studies suggest that diet-related fructose intake exceeding the amount contained in vegetables and fruits lead to an increase of hepatic lipogenesis. Thus, further studies to clarify the protective contribution of low-fructose intake to positively influence NAFLD in industrial population are urgently required.

Low-intensity exercise diverts cardiac fatty acid metabolism from triacylglycerol synthesis to beta oxidation in fructose-fed rats

Context Excessive fructose consumption causes ectopic lipid storage leading to metabolic disorders and cardiovascular diseases associated with defective substrate utilisation in the heart. Objective Examining the preventive impact of low-intensity exercise on alterations related to fructose-rich diet (FRD) on cardiac fatty acid (FA) transport and metabolism. Materials and methods Male Wistar rats were divided into control and two groups that received 10% fructose for 9 weeks, one of which was additionally exposed to exercise. Results FRD elevated plasma and cardiac TAG, FATP1 in plasma membrane, Lipin 1 in microsomes and HSL mRNA, while mitochondrial CPT1 was decreased. Exercise decreased plasma free FA level, raised CD36 in plasma membrane and FATP1 in lysate, mitochondrial CPT1 and decreased microsomal Lipin 1 in fructose-fed rats. Conclusions FRD changed plasma lipids and augmented partitioning of FA to TAG storage in the heart, whereas exercise in FRD rats switched metabolism of FA towards β-oxidation.

Excess dietary fructose does not alter gut microbiota or permeability in humans: A pilot randomized controlled study

Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of chronic liver disease that accompanies obesity and the metabolic syndrome. Excess fructose consumption can initiate or exacerbate NAFLD in part due to a consequence of impaired hepatic fructose metabolism. Preclinical data emphasized that fructose-induced altered gut microbiome, increased gut permeability, and endotoxemia play an important role in NAFLD, but human studies are sparse. The present study aimed to determine if two weeks of excess fructose consumption significantly alters gut microbiota or permeability in humans. We performed a pilot double-blind, cross-over, metabolic unit study in 10 subjects with obesity (body mass index [BMI] 30-40mg/kg/m2). Each arm provided 75grams of either fructose or glucose added to subjects' individual diets for 14 days, substituted isocalorically for complex carbohydrates, with a 19-day wash-out period between arms. Total fructose intake provided in the fructose arm of the study totaled a mean of 20.1% of calories. Outcome measures included fecal microbiota distribution, fecal metabolites, intestinal permeability, markers of endotoxemia, and plasma metabolites. Routine blood, uric acid, liver function, and lipid measurements were unaffected by the fructose intervention. The fecal microbiome (including Akkermansia muciniphilia), fecal metabolites, gut permeability, indices of endotoxemia, gut damage or inflammation, and plasma metabolites were essentially unchanged by either intervention. In contrast to rodent preclinical findings, excess fructose did not cause changes in the gut microbiome, metabolome, and permeability as well as endotoxemia in humans with obesity fed fructose for 14 days in amounts known to enhance NAFLD.

The role of microRNA-33 as a key regulator in hepatic lipogenesis signaling and a potential serological biomarker for NAFLD with excessive dietary fructose consumption in C57BL/6N mice.

Limited studies reported mechanisms by which microRNAs (miRNA) are interlinked in the etiology of fructose-induced non-alcoholic fatty liver disease (NAFLD). Here, we aimed to investigate the significance of miRNAs in fructose-induced NAFLD pathogenesis through unbiased approaches. In experiment I, C57BL/6N mice were fed either water or 34% fructose for six weeks ad libitum. In experiment II, time course effects of fructose intervention were monitored using the same conditions; mice were killed at the baseline, fourth, and sixth weeks. Bioinformatic analyses for hepatic proteomics revealed that SREBP1 is the most significant upstream regulator influenced by fructose; miR-33-5p (miR-33) was identified as the key miRNA responsible for SREBP1 regulation upon fructose intake, which was validated by in vitro transfection assay. In experiment II, we confirmed that the longer mice consumed fructose, the more severe liver injury markers (e.g., serum AST) appeared. Moreover, hepatic Srebp1 mRNA expression was increased depending upon the duration of fructose consumption. Hepatic miR-33 was time-dependently decreased by fructose while serum miR-33 expression was increased; these observations indicated that miR-33 from the liver might be released upon cell damage. Finally we observed that fructose-induced ferroptosis might be a cause of liver toxicity, resulting from oxidative damage. Collectively, our findings suggest that fructose-induced oxidative damage induces ferroptosis, and miR-33 could be used as a serological biomarker of fructose-induced NAFLD.

The effects of different types of aquatic exercise training interventions on a high-fructose diet-fed mice.

Gradual weight gain in modern people and a lowering onset age of metabolic disease are highly correlated with the intake of sugary drinks and sweets. Long-term excessive fructose consumption can lead to hyperglycemia, hyperlipidemia and accumulation of visceral fat. Abdominal obesity is more severe in females than in males. In this study, we used a high-fructose-diet-induced model of obesity in female mice. We investigated the effects of aquatic exercise training on body weight and body composition. After 1 week of acclimatization, female ICR mice were randomly divided into two groups: a normal group (n=8) fed standard diet (control), and a high-fructose diet (HFD) group (n=24) fed a HFD. After 4 weeks of induction followed by 4 weeks of aquatic exercise training, the 24 obese mice were divided into 3 groups (n=8 per group): HFD with sedentary control (HFD), HFD with aquatic strength exercise training (HFD+SE), and HFD with aquatic aerobic exercise training (HFD+AE). We conducted serum biochemical profile analysis, weighed the white adipose tissue, and performed organ histopathology. After 4 weeks of induction and 4 weeks of aquatic exercise training, there was no significant difference in body weight among the HFD, HFD+SE and HFD+AE groups. Serum triglyceride (TG), AST, ALT, and uric acid level were significantly lower in the HFD+SE and HFD+AE groups than in the HFD group. The weight of the perirenal fat pad was significantly lower in the HFD+AE group than in the HFD group. Hepatic TG and total cholesterol (TC) were significantly lower in the HFD+AE group than in the other groups. Long-term intake of a high-fructose diet can lead to obesity and increase the risk of metabolic disease. Based on our findings, we speculate that aquatic exercise training can effectively promote health and fitness. However, aquatic aerobic exercise training appears to have greater benefits than aquatic strength exercise training.

The relationship between excessive dietary fructose consumption and paediatric fatty liver disease.

The global prevalence of non-alcoholic fatty liver disease (NAFLD) in children and adolescents is escalating and currently represents the most common chronic liver disease in the paediatric population. NAFLD is associated with high daily caloric intake and sedentary behaviour, with excessive consumption of added sugar emerging as an important contributor to NAFLD risk in children. This is a particularly important factor for adolescents with obesity, who are the heaviest consumers of added sugar. Table sugar, or sucrose, is a disaccharide comprised of fructose and glucose, yet only fructose has been strongly linked to NAFLD pathogenesis largely due to the unique characteristics of its metabolism and detrimental effects on key metabolic pathways. To date, the relationship between excessive fructose intake and risk of NAFLD in children and adolescents remains incompletely understood, and it is not yet known whether fructose actually causes NAFLD or instead exacerbates hepatic fat accumulation and possible hepatocellular injury only within the context of cardiometabolic factors. The purpose of this review is to summarize recent studies linking fructose consumption with NAFLD in the paediatric population and integrate results from interventional studies of fructose restriction in children and adolescents on NAFLD and related metabolic markers. Given the overall positive impact of lifestyle modifications in the management of paediatric NAFLD, reduction of added sugar consumption may represent an important, early opportunity to mitigate or prevent NAFLD in high-risk children and adolescents.

Fructosa, un factor clave modificable en la patogenia del síndrome metabólico, la esteatosis hepática y la obesidad

This review summarizes the specific role that excess fructose consumption (beyond its calories) may have in the development of MetS, NAFLD and its association with obesity. The effects of fructose (compared to glucose) on hepatic steatosis are discussed as well as their consequence: insulin resistance and hypertriglyceridemia. Unlike glucose, more than 80% ingested fructose stays in the liver, and due to lack of fine metabolic regulation, high fructose flows consume ATP generating uric acid, produce toxic metabolites such as ceramides and methylglyoxal and activate lipid synthesis. In addition, the study analyzes the effects of fructose on adipose tissue, cortisol activation and hormones involved in satiety control, all of which are affected by fructose consumption. The initial hepatic insulin resistance is complicated by systemic insulin resistance, which generates leptin resistance and a hyperphagia cycle. These results underscore the need for clinical and educational interventions within the population to regulate / reduce fructose consumption, especially in children and adolescents, their main consumers.

Intestinal fructose absorption: Modulation and relation to human diseases

BackgroundFructose is a hexose sugar found naturally in our diet and excessive fructose consumption has been documented in humans over the last decades. Fructose absorption in the small intestine is a highly regulated process and GLUT5 plays an essential role in this process, but GLUT2 is also involved. MethodsIn this review, we will describe the multiple mechanisms involved in the regulation of intestinal fructose absorption and the effects of excessive consumption of this sugar on human health. ResultsExcessive fructose intake is associated with a growing incidence of certain diseases, including obesity, type 2 diabetes, non-alcoholic fatty liver disease, cardiac disease, gastrointestinal disorders, and cancer. It is also associated with changes in gut integrity and microbiota. ConclusionsHigh fructose consumption is associated with the development of characteristics of metabolic syndrome and of other diseases such as cardiomyopathies, kidney disease and tumor growth, in both humans and rodents So, modulation of GLUT5- and/or GLUT2-mediated intestinal fructose absorption might provide a novel pharmacologic strategy for the treatment of these diseases. However, most of the data on high fructose consumption has been obtained in rodent models, and so more studies are needed in order to fully confirm these observations in humans.

Hepatic miR-192-3p reactivation alleviates steatosis by targeting glucocorticoid receptor.

Background & AimsThe paradox of hepatic insulin resistance describes the inability for liver to respond to bioenergetics hormones in suppressing gluconeogenesis whilst maintaining lipid synthesis. Here, we report the deficiency of miR-192-3p in the livers of mice with diabetes and its role in alleviating hepatic steatosis.MethodsAs conventional pre-microRNA (miRNA) stem-loop overexpression only boosts guiding strand (i.e. miR-192-5p) expression, we adopted an artificial AAV(DJ)-directed, RNA Pol III promoter-driven miRNA hairpin construct for star-strand-specific overexpression in the liver. Liver steatosis and insulin resistance markers were evaluated in primary hepatocytes, mice with diabetes, and mice with excessive carbohydrate consumption.ResultsFunctional loss of miR-192-3p in liver exacerbated hepatic micro-vesicular steatosis and insulin resistance in either mice with diabetes or wild-type mice with excessive fructose consumption. Liver-specific overexpression of miR-192-3p effectively halted hepatic steatosis and ameliorated insulin resistance in these mice models. Likewise, hepatocytes overexpressing miR-192-3p exhibited improved lipid accumulation, accompanied with decreases in lipogenesis and lipid-accumulation-related transcripts. Mechanistically, glucocorticoid receptor (GCR, also known as nuclear receptor subfamily 3, group C, member 1 [NR3C1]) was demonstrated to be negatively regulated by miR-192-3p. The effect of miR-192-3p on mitigating micro-vesicular steatosis was ablated by the reactivation of NR3C1.ConclusionsThe star strand miR-192-3p was an undermined glycerolipid regulator involved in controlling fat accumulation and insulin sensitivity in liver through blockade of hepatic GCR signalling; this miRNA may serve as a potential therapeutic option for the common co-mobility of diabetic mellitus and fatty liver disease.Lay summaryThe potential regulatory activity of star strand microRNA (miRNA) species has been substantially underestimated. In this study, we investigate the role and mechanism of an overlooked star strand miRNA (miR-192-3p) in regulating hepatic steatosis and insulin signalling in the livers of mice with diabetes and mice under excessive carbohydrate consumption.

SHR-Zbtb16 minimal congenic strain reveals nutrigenetic interaction between Zbtb16 and high-sucrose diet.

Both prenatal and postnatal excessive consumption of dietary sucrose or fructose was shown to be detrimental to health and contributing to pathogenesis of metabolic syndrome. Our knowledge of genetic determinants of individual sensitivity to sucrose-driven metabolic effects is limited. In this study, we have tested the hypothesis that a variation of metabolic syndrome-related gene, Zbtb16 (Zinc Finger and BTB Domain Containing 16 will affect the reaction to high-sucrose diet (HSD) content in "matched" nutritional exposition settings, i.e. maternal HSD with re-exposition to HSD in adulthood vs. standard diet. We compared metabolic profiles of adult males of spontaneously hypertensive rats (SHR) and a single-gene, minimal congenic strain SHR-Zbtb16 fed either standard diet or exposed to HSD prenatally throughout gestation and nursing and again at the age of 6 months for the period of 14 days. HSD exposition led to increased adiposity in both strains and decrease of glucose tolerance and cholesterol (Ch) concentrations in majority of low-density lipoprotein (LDL) particle classes and in very large and large high-density lipoprotein (HDL) in SHR-Zbtb16 male offspring. There was a similar pattern of HSD-induced increase of triacylglycerols in chylomicrons and very low-density lipoprotein (VLDL) of both strains, though the increase of (triacylglycerol) TAG content was clearly more pronounced in SHR. We observed significant STRAIN*DIET interactions for the smallest LDL particles as their TAG content decreased in SHR-Zbtb16 and did not change in SHR in response to HSD. In summary, we provide evidence of nutrigenetic interaction between Zbtb16 and HSD in context of pathogenesis of metabolic syndrome.

The small intestine shields the liver from fructose-induced steatosis.

Per capita fructose consumption has increased 100-fold over the last century1. Epidemiological studies suggest that excessive fructose consumption, and especially consumption of sweet drinks, is associated with hyperlipidaemia, non-alcoholic fatty liver disease, obesity and diabetes2-7. Fructose metabolism begins with its phosphorylation by the enzyme ketohexokinase (KHK), which exists in two alternatively spliced forms8. The more active isozyme, KHK-C, is expressed most strongly in the liver, but also substantially in the small intestine9,10 where it drives dietary fructose absorption and conversion into other metabolites before fructose reaches the liver11-13. It is unclear whether intestinal fructose metabolism prevents or contributes to fructose-induced lipogenesis and liver pathology. Here we show that intestinal fructose catabolism mitigates fructose-induced hepatic lipogenesis. In mice, intestine-specific KHK-C deletion increases dietary fructose transit to the liver and gut microbiota and sensitizes mice to fructose's hyperlipidaemic effects and hepatic steatosis. In contrast, intestine-specific KHK-C overexpression promotes intestinal fructose clearance and decreases fructose-induced lipogenesis. Thus, intestinal fructose clearance capacity controls the rate at which fructose can be safely ingested. Consistent with this, we show that the same amount of fructose is more strongly lipogenic when drunk than eaten, or when administered as a single gavage, as opposed to multiple doses spread over 45 min. Collectively, these data demonstrate that fructose induces lipogenesis when its dietary intake rate exceeds the intestinal clearance capacity. In the modern context of ready food availability, the resulting fructose spillover drives metabolic syndrome. Slower fructose intake, tailored to intestinal capacity, can mitigate these consequences.

Meeting Sugar Intake Recommendation Is Protective Against Health Parameters Associated With Chronic Disease in College Students

Abstract Objectives Metabolic Syndrome (MetS) is an accumulation of health factors that increase an individual's chance of chronic diseases and disabling conditions, such as type II diabetes, heart attack, and stroke. Multiple studies have shown a positive association between sugar consumption and aggravation of parameters related to MetS. We analyzed the effects of meeting the acceptable macronutrient range (AMDR) for sugar consumption on MetS parameters among college students. We hypothesized that meeting this recommendation would be associated with positive outcomes for MetS parameters. Methods Plasma lipids, glucose, and waist circumference (WC) were measured in 167 Weber State Students (ages 18–65). A two-day diet record was collected and analyzed using diet and wellness plus. Participants were separated into two groups, based on whether or not they met the AMDR of consuming less than 25% of total calories from sugar. Mean comparisons between low sugar (LS) and high sugar (HS) consumers were performed using independent samples t-test. Results 63% of participants met the sugar AMDR recommendation. LS group participants presented lower WC (75.8 ± 10.5 vs. 75.5 ± 11.5 cm, P = 0.03) and plasma triglycerides (TG) (76.0 ± 47.6 vs. 121.6 ± 99.9 mg/dL, P = 0.001) compared to their HS counterparts. In addition, we observed a positive trend in the high-density lipoprotein cholesterol (HDL-C) (52.7 ± 16.9 vs 47.59 ± 17.14, P = 0.06) levels of the HS group, compared to the LS group. Conclusions We observed that the percentage of total calories consumed from sugar is an important modulator of circulating triglycerides and central adiposity. This is in accordance with previous studies, which show that excess fructose consumption exerts adipogenic effects, and can trigger de novo lipogenesis in the liver, resulting in increased triglyceride production and secretion. Funding Sources Weber State University Office of Undergraduate Research.

Anomalous AMPK-regulated angiotensin AT1R expression and SIRT1-mediated mitochondrial biogenesis at RVLM in hypertension programming of offspring to maternal high fructose exposure

BackgroundTissue oxidative stress, sympathetic activation and nutrient sensing signals are closely related to adult hypertension of fetal origin, although their interactions in hypertension programming remain unclear. Based on a maternal high-fructose diet (HFD) model of programmed hypertension, we tested the hypothesis that dysfunction of AMP-activated protein kinase (AMPK)-regulated angiotensin type 1 receptor (AT1R) expression and sirtuin1 (SIRT1)-dependent mitochondrial biogenesis contribute to tissue oxidative stress and sympathoexcitation in programmed hypertension of young offspring.MethodsPregnant female rats were randomly assigned to receive normal diet (ND) or HFD (60% fructose) chow during pregnancy and lactation. Both ND and HFD offspring returned to ND chow after weaning, and blood pressure (BP) was monitored from age 6 to 12 weeks. At age of 8 weeks, ND and HFD offspring received oral administration of simvastatin or metformin; or brain microinfusion of losartan. BP was monitored under conscious condition by the tail-cuff method. Nutrient sensing molecules, AT1R, subunits of NADPH oxidase, mitochondrial biogenesis markers in rostral ventrolateral medulla (RVLM) were measured by Western blot analyses. RVLM oxidative stress was measured by fluorescent probe dihydroethidium and lipid peroxidation by malondialdehyde assay. Mitochondrial DNA copy number was determined by quantitative real-time polymerase chain reaction.ResultsIncreased systolic BP, plasma norepinephrine level and sympathetic vasomotor activity were exhibited by young HFD offspring. Reactive oxygen species (ROS) level was also elevated in RVLM where sympathetic premotor neurons reside, alongside augmented protein expressions of AT1R and pg91phox subunit of NADPH oxidase, decrease in superoxide dismutase 2; and suppression of transcription factors for mitochondrial biogenesis, peroxisome proliferator-activated receptor γ co-activator α (PGC-1α) and mitochondrial transcription factor A (TFAM). Maternal HFD also attenuated AMPK phosphorylation and protein expression of SIRT1 in RVLM of young offspring. Oral administration of a HMG-CoA reductase inhibitor, simvastatin, or an AMPK activator, metformin, to young HFD offspring reversed maternal HFD-programmed increase in AT1R and decreases in SIRT1, PGC-1α and TFAM; alleviated ROS production in RVLM, and attenuated sympathoexcitation and hypertension.ConclusionDysfunction of AMPK-regulated AT1R expression and SIRT1-mediated mitochondrial biogenesis may contribute to tissue oxidative stress in RVLM, which in turn primes increases of sympathetic vasomotor activity and BP in young offspring programmed by excessive maternal fructose consumption.

Early menarche and its consequence in Korean female: reducing fructose intake could be one solution.

The mean age at menarche (AAM) of Korean females has been rapidly decreasing over the last 50 years; currently, the prevalence of early menarche (<12 years) is 22.3%. Female adolescents who experience early menarche are known to be at greater risk of psychosocial and behavioral problems along with several physical health problems such as menstrual problems. They also tend to achieve a shorter final height and develop obesity. Population-based Korean studies have shown a strong association between early menarche and the risk of obesity, insulin resistance, metabolic syndrome, nonalcoholic fatty liver disease, diabetes, breast cancer, and cardiovascular disease in adulthood. Although the exact mechanism of how early menarche causes cardiometabolic derangement in later adulthood is unknown, childhood obesity and insulin resistance might be major contributors. Recent studies demonstrated that an excessive consumption of fructose might underlie the development of obesity and insulin resistance along with an earlier AAM. A positive association was observed between sugar-sweetened beverages (a major source of fructose) intake and obesity, metabolic syndrome, insulin resistance, and cardiometabolic risk in Korean females. In pediatrics, establishing risk factors is important in preventing disease in later life. In this regard, early menarche is a simple and good marker for the management of cardiometabolic diseases in adulthood. Decreasing one’s fructose intake might prevent early menarche as well as the development of obesity, insulin resistance, and cardiometabolic diseases.

HMGB1‐TLR4 in The Brainstem Nuclei Mediates Fructose‐induced Metabolic Syndrome

The metabolic syndrome caused by excessive consumption of fructose is one of a variety of abnormal physiological phenomena, which is related to cardiovascular diseases. Our previous study reported that hypertension and central insulin resistance in WKY rats were caused by fructose intake. Several studies have been reported that the intake of fructose causes central inflammation. Toll‐like receptor 4 (TLR4) play a key role of innate immune signaling and has been implicated in fructose‐induced metabolic syndrome rats. We analyzed systolic blood pressure, biochemical parameter, and TLR4‐signaling pathway of WKY rats and fructose‐intake rats treated with vehicle or CLI‐095 (12 mg×d−1 for 14 days through osmotic mini‐pump). We found that the systolic blood pressure of rats treated CLI‐095 was improved to the normotensive group. The body weight change was recovered to the rats treated with the vehicle. Serum glucose treated with CLI‐095 was restored and stabilized compared with the fructose group. Immunoblotting results showed HMGB1 and TLR4 rather than TLR2, TLR7, TLR9 were induced in the brainstem nuclei area. MyD88, phosphorylated TGF beta‐activated kinase 1 (TAK1) and JNK were inhibited in the CLI‐095 group. Neuroinflammatory indicator iNOS was reduced in the therapy group. These data demonstrated that TLR4 in the central brain participates in the regulation of blood pressure, glucose, and body weight, which suggested HMGB1‐TLR4 might be a potential target for therapeutic interventions in the condition with metabolic syndrome combined with neuroinflammation.Support or Funding InformationThis work was supported by the Ministry of Science and Technology grants 107‐2320‐B‐075B‐001 (to P.W.C.) and 107‐2320‐B‐075B‐002‐MY2 (to C.J.T.) and Kaohsiung Veterans General Hospital grants VGHKS108‐162 (to Y.T.L.) and VGHUST108‐G3‐1‐3 (to Y.T.L.).

Dietary Fructose Intake and Hippocampal Structure and Connectivity during Childhood.

In rodent literature, there is evidence that excessive fructose consumption during development has a detrimental impact on hippocampal structure and function. In this study of 103 children ages 7–11 years old, we investigated whether dietary fructose intake was related to alterations in hippocampal volume and connectivity in humans. To examine if these associations were specific to fructose or were related to dietary sugars intake in general, we explored relationships between dietary intake of added sugars and the monosaccharide, glucose, on the same brain measures. We found that increased dietary intake of fructose, measured as a percentage of total calories, was associated with both an increase in the volume of the CA2/3 subfield of the right hippocampus and increased axial, radial, and mean diffusivity in the prefrontal connections of the right cingulum. These findings are consistent with the idea that increased fructose consumption during childhood may be associated with an inflammatory process, and/or decreases or delays in myelination and/or pruning. Increased habitual consumption of glucose or added sugar in general were associated with an increased volume of right CA2/3, but not with any changes in the connectivity of the hippocampus. These findings support animal data suggesting that higher dietary intake of added sugars, particularly fructose, are associated with alterations in hippocampal structure and connectivity during childhood.