Integrated omics analysis reveals sirtuin signaling is central to hepatic response to a high fructose diet.
BMC genomics
BACKGROUND:Dietary high fructose (HFr) is a known metabolic disruptor contributing to development of obesity and diabetes in Western societies. Initial molecular changes from exposure to HFr on liver metabolism may be essential to understand the perturbations leading to insulin resistance and abnormalities in lipid and carbohydrate metabolism. We studied vervet monkeys (Clorocebus aethiops sabaeus) fed a HFr (n=5) or chow diet (n=5) for 6 weeks, and obtained clinical measures of liver function, blood insulin, cholesterol and triglycerides. In addition, we performed untargeted global transcriptomics, proteomics, and metabolomics analyses on liver biopsies to determine the molecular impact of a HFr diet on coordinated pathways and networks that differed by diet. RESULTS:We show that integration of omics data sets improved statistical significance for some pathways and networks, and decreased significance for others, suggesting that multiple omics datasets enhance confidence in relevant pathway and network identification. Specifically, we found that sirtuin signaling and a peroxisome proliferator activated receptor alpha (PPARA) regulatory network were significantly altered in hepatic response to HFr. Integration of metabolomics and miRNAs data further strengthened our findings. CONCLUSIONS:Our integrated analysis of three types of omics data with pathway and regulatory network analysis demonstrates the usefulness of this approach for discovery of molecular networks central to a biological response. In addition, metabolites aspartic acid and docosahexaenoic acid (DHA), protein ATG3, and genes ATG7, and HMGCS2 link sirtuin signaling and the PPARA network suggesting molecular mechanisms for altered hepatic gluconeogenesis from consumption of a HFr diet.
10.1186/s12864-021-08166-0
Exposure to high fructose corn syrup during adolescence in the mouse alters hepatic metabolism and the microbiome in a sex-specific manner.
Bhat Shazia F,Pinney Sara E,Kennedy Katherine M,McCourt Cole R,Mundy Miles A,Surette Michael G,Sloboda Deborah M,Simmons Rebecca A
The Journal of physiology
KEY POINTS:The prevalence of obesity and non-alcoholic fatty liver disease in children is dramatically increasing at the same time as consumption of foods with a high sugar content. Intake of high fructose corn syrup (HFCS) is a possible aetiology as it is thought to be more lipogenic than glucose. In a mouse model, HFCS intake during adolescence increased fat mass and hepatic lipid levels in male and female mice. However, only males showed impaired glucose tolerance. Multiple metabolites including lipids, bile acids, carbohydrates and amino acids were altered in liver in a sex-specific manner at 6 weeks of age. Some of these changes were also present in adulthood even though HFCS exposure ended at 6 weeks. HFCS significantly altered the gut microbiome, which was associated with changes in key microbial metabolites. These results suggest that HFCS intake during adolescence has profound metabolic changes that are linked to changes in the microbiome and these changes are sex-specific. ABSTRACT:The rapid increase in obesity, diabetes and fatty liver disease in children over the past 20 years has been linked to increased consumption of high fructose corn syrup (HFCS), making it essential to determine the short- and long-term effects of HFCS during this vulnerable developmental window. We hypothesized that HFCS exposure during adolescence significantly impairs hepatic metabolic signalling pathways and alters gut microbial composition, contributing to changes in energy metabolism with sex-specific effects. C57bl/6J mice with free access to HFCS during adolescence (3-6 weeks of age) underwent glucose tolerance and body composition testing and hepatic metabolomics, gene expression and triglyceride content analysis at 6 and 30 weeks of age (n = 6-8 per sex). At 6 weeks HFCS-exposed mice had significant increases in fat mass, glucose intolerance, hepatic triglycerides (females) and de novo lipogenesis gene expression (ACC, DGAT, FAS, ChREBP, SCD, SREBP, CPT and PPARα) with sex-specific effects. At 30 weeks, HFCS-exposed mice also had abnormalities in glucose tolerance (males) and fat mass (females). HFCS exposure enriched carbohydrate, amino acid, long chain fatty acid and secondary bile acid metabolism at 6 weeks with changes in secondary bile metabolism at 6 and 30 weeks. Microbiome studies performed immediately before and after HFCS exposure identified profound shifts of microbial species in male mice only. In summary, short-term HFCS exposure during adolescence induces fatty liver, alters important metabolic pathways, some of which continue to be altered in adulthood, and changes the microbiome in a sex-specific manner.
10.1113/JP280034
Untargeted metabolomics and phenotype data indicate the therapeutic and prophylactic potential of Lindl. towards high-fat high-fructose-induced metabolic syndrome in rats.
Molecular omics
The present study evaluated the therapeutic potential of the medicinal plant Lindl. against metabolic syndrome in male SD rats fed with a high-fat high-fructose (HFHF) diet. Methanolic extract of Lindl. (250 mg kg body weight p.o.) was administrated to the HFHF-fed rats daily for 20 weeks. Blood samples were collected, and blood glucose levels and relevant biochemical parameters were analysed and used for the assessment of metabolic disease phenotypes. In this study, decreased HFHF diet-induced phenotypes of metabolic syndrome, , obesity, blood glucose level, hepatic triglycerides, free fatty acids, and insulin resistance. Liquid chromatography-mass spectrometry-based metabolomics was done to study the dynamics of metabolic changes in the serum during disease progression in the presence and absence of the treatment. Furthermore, multivariate data analysis approaches have been employed to identify metabolites responsible for disease progression. Lindl. plant extract restored the metabolites that are involved in the biosynthesis and degradation of amino acids, fatty acid metabolism and vitamin metabolism. Interestingly, the results depicted that the treatment with the plant extract restored the levels of acetylated amino acids and their derivatives, which are involved in the regulation of beta cell function, glucose homeostasis, insulin secretion, and metabolic syndrome phenotypes. Furthermore, we observed restoration in the levels of indole derivatives and -acetylgalactosamine with the treatment, which indicates a cross-talk between the gut microbiome and the metabolic syndrome. Therefore, the present study revealed the potential mechanism of Lindl. extract to prevent metabolic syndrome in rats.
10.1039/d3mo00104k
The combination of metagenome and metabolome to compare the differential effects and mechanisms of fructose and sucrose on the metabolic disorders and gut microbiota and .
Food & function
Sucrose and fructose are the most commonly used sweeteners in the modern food industry, but there are few comparative studies on the mechanisms by which fructose and sucrose affect host health. The aim of the present study was to explain the different effects of fructose and sucrose on host metabolism from the perspective of gut microbiota. Mice were fed for 16 weeks with normal drinking water (CON), 30% fructose drinking water (CF) and 30% sucrose drinking water (SUC). Compared with fructose treatment, sucrose caused significantly higher weight gain, epididymal fat deposition, hepatic steatosis, and jejunum histological injury. Sucrose increased the abundance of LPS-producing bacteria which was positively correlated with obesity traits, while fructose increased the abundance of . An fermentation experiment also showed that fructose increased the abundance of , while sucrose increased the abundance of and . In addition, combined with microbial functional analysis and metabolomics data, fructose led to the enhancement of carbohydrate metabolism and TCA cycle capacity, and increased the production of glutamate. The cross-cooperation network greatly influenced the microbiota (, ), metabolites (glutamate, fructose 1,6-biosphosphate, citric acid), and genes encoding enzymes (pyruvate kinase, 6-phosphofructokinase 1, fructokinase, lactate dehydrogenase, aconitate hydratase, isocitrate dehydrogenase 3), suggesting that they may be the key differential factors in the process of fructose and sucrose catabolism. Therefore, the changes in gut microbiome mediated by fructose and sucrose are important reasons for their differential effects on host health and metabolism.
10.1039/d3fo02246c
High intake of dietary fructose in overweight/obese teenagers associated with depletion of and in gut microbiome.
Jones Roshonda B,Alderete Tanya L,Kim Jeniffer S,Millstein Joshua,Gilliland Frank D,Goran Michael I
Gut microbes
: A western high fat, high carbohydrate diet has been shown to be associated with decreased gut bacterial diversity and reductions in beneficial bacteria. This gut bacteria dysbiosis could develop in early life and contribute to chronic disease risk such as obesity, type 2 diabetes and non-alcoholic fatty liver disease.: To determine how dietary macronutrients are associated with the relative abundance of gut bacteria in healthy adolescents.: Fifty-two obese participants (12-19 years) from two studies, many who were primarily of Hispanic background, provided fecal samples for 16S rRNA gene sequencing. Dietary macronutrients were assessed using 24-hour diet recalls and body composition was assessed using DEXA. General regression models assuming a negative binomial distribution were used to examine the associations between gut bacteria and dietary fiber, saturated fat, unsaturated fats, protein, added sugar, total sugar and free fructose after adjusting for age, gender, race/ethnicity, body fat percentage, study and caloric intake.: The genera (Benjamini-Hochberg (BH) corrected -value = 0.10) and (BH corrected -value = 0.04) were inversely associated with dietary fructose intake. There were no other significant associations between abundances of gut microbes and other dietary macronutrients, including fiber, fat, protein, total sugar or added sugar.: High dietary fructose was associated with lower abundance of the beneficial microbes and , which are involved with carbohydrate metabolism.
10.1080/19490976.2019.1592420
Comparative profiling of gut microbiota and metabolome in diet-induced obese and insulin-resistant C57BL/6J mice.
Biochimica et biophysica acta. Molecular cell research
Diet-based models are commonly used to investigate obesity and related disorders. We conducted a comparative profiling of three obesogenic diets HFD, high fat diet; HFHF, high fat high fructose diet; and HFCD, high fat choline deficient diet to assess their impact on the gut microbiome and metabolome. After 20 weeks, we analyzed the gut microbiota and metabolomes of liver, plasma, cecal, and fecal samples. Fecal and plasma bile acids (BAs) and fecal short-chain fatty acids (SCFAs) were also examined. Significant changes were observed in fecal and cecal metabolites, with increased Firmicutes and decreased Bacteroidetes in the HFD, HFHF, and HFCD-fed mice compared to chow and LFD (low fat diet)-fed mice. Most BAs were reduced in plasma and fecal samples of obese groups, except taurocholic acid, which increased in HFCD mice's plasma. SCFAs like acetate and butyrate significantly decreased in obesogenic diet groups, while propionic acid specifically decreased in the HFCD group. Pathway analysis revealed significant alterations in amino acid, carbohydrate metabolism, and nucleic acid biosynthesis pathways in obese mice. Surprisingly, even LFD-fed mice showed distinct changes in microbiome and metabolite profiles compared to the chow group. This study provides insights into gut microbiome dysbiosis and metabolite alterations induced by obesogenic and LFD diets in various tissues. These findings aid in selecting suitable diet models to study the role of the gut microbiome and metabolites in obesity and associated disorders, with potential implications for understanding similar pathologies in humans.
10.1016/j.bbamcr.2023.119643
A High-Fat High-Fructose Diet Dysregulates the Homeostatic Crosstalk Between Gut Microbiome, Metabolome, and Immunity in an Experimental Model of Obesity.
Molecular nutrition & food research
SCOPE:Ample evidence supports the prominent role of gut-liver axis in perpetuating pathological networks of high-fat high-fructose (HFF) diet induced metabolic disorders, however, the molecular mechanisms are still not fully understood. Herein, this study aims to present a holistic delineation and scientific explanation for the crosstalk between the gut and liver, including the potential mediators involved in orchestrating the metabolic and immune systems. METHODS AND RESULTS:An experimental obesity-associated metaflammation rat model is induced with a HFF diet. An integrative multi-omics analysis is then performed. Following the clues illustrated by the multi-omics discoveries, putative pathways are subsequently validated by RT-qPCR and Western blotting. HFF diet leads to obese phenotypes in rats, as well as histopathological changes. Integrated omics analysis shows that there exists a strong interdependence among gut microbiota composition, intestinal metabolites, and innate immunity regulation in the liver. Some carboxylic acids may contribute to gut-liver communication. Moreover, activation of the hepatic LPS-TLR4 pathway in obesity is confirmed. CONCLUSION:HFF-intake disturbs gut flora homeostasis. Crosstalk between gut microbiota and innate immune system mediates hepatic metaflammation in obese rats, associated with LPS-TLR4 signaling pathway activation. Moreover, α-hydroxyisobutyric acid and some other organic acids may play a role as messengers in the liver-gut axis.
10.1002/mnfr.202100950
Fructose corn syrup induces inflammatory injury and obesity by altering gut microbiota and gut microbiota-related arachidonic acid metabolism.
The Journal of nutritional biochemistry
Excessive fructose corn syrup (FCS) intake brings a series of health problems. The aim of the present study was to explore the mechanism of FCS-induced metabolic disorders from the perspective of gut microbiota. Mice were fed for 16 weeks with normal or 30% FCS drinking water. Compared to the control group, FCS caused significantly higher fat deposition, hepatic steatosis, liver and intestinal inflammatory damages (P<.05). FCS increased the abundance of Muribaculaceae in vivo and in vitro, which was positively correlated with the indices of metabolic disorders (P<.05). In vivo and in vitro data indicated that FCS enhanced the microbial function involved in pentose phosphate pathway and arachidonic acid metabolism, metabolomics further demonstrated that FCS led to an increase in prostaglandins (the catabolites of arachidonic acid) (P<.05). Our study confirmed that FCS can directly promote gut microbiota to synthesize inflammatory factor prostaglandins, which provides new insights and directions for the treatment of FCS-induced metabolic disorders and inflammation.
10.1016/j.jnutbio.2023.109527
Sesamolin Alleviates Nonalcoholic Fatty Liver Disease through Modulating Gut Microbiota and Metabolites in High-Fat and High-Fructose Diet-Fed Mice.
International journal of molecular sciences
Nonalcoholic fatty liver disease (NAFLD) has become a major public health problem. The effects of sesamolin on obesity-associated NAFLD and its possible mechanism are still poorly understood. The present study investigated the effects of sesamolin on NAFLD and changes in gut microbiota and serum metabolites in high-fat and high-fructose (HF-HF) diet-fed mice. Mice with NAFLD were treated with or without sesamolin. Sesamolin effectively suppressed obesity-associated metabolic disorder, attenuated hepatic steatosis and the infiltration of inflammatory cells, and decreased levels of hepatic proinflammatory cytokines. Sesamolin also altered the composition of gut microbiota at the genus level. Additionally, differential serum metabolite biomarkers identified in an untargeted metabolomics analysis showed that sesamolin changed the levels of metabolites and influenced metabolomics pathways including caffeine metabolism, steroid hormone biosynthesis, and cysteine and methionine metabolism. Changes in metabolite biomarkers and the abundances of , , , , and are highly correlated with those factors involved in the progression of NAFLD. These results are important in deciphering new mechanisms by which changes in bacteria and metabolites in sesamolin treatment might be associated with the alleviation of obesity-associated NAFLD in HF-HF diet-fed mice. Thus, sesamolin may be a potential compound for obesity-associated NAFLD treatment.
10.3390/ijms232213853
Fructose-Induced Intestinal Microbiota Shift Following Two Types of Short-Term High-Fructose Dietary Phases.
Beisner Julia,Gonzalez-Granda Anita,Basrai Maryam,Damms-Machado Antje,Bischoff Stephan C
Nutrients
High consumption of fructose and high-fructose corn syrup is related to the development of obesity-associated metabolic diseases, which have become the most relevant diet-induced diseases. However, the influences of a high-fructose diet on gut microbiota are still largely unknown. We therefore examined the effect of short-term high-fructose consumption on the human intestinal microbiota. Twelve healthy adult women were enrolled in a pilot intervention study. All study participants consecutively followed four different diets, first a low fructose diet (< 10 g/day fructose), then a fruit-rich diet (100 g/day fructose) followed by a low fructose diet (10 g/day fructose) and at last a high-fructose syrup (HFS) supplemented diet (100 g/day fructose). Fecal microbiota was analyzed by 16S rRNA sequencing. A high-fructose fruit diet significantly shifted the human gut microbiota by increasing the abundance of the phylum , in which beneficial butyrate producing bacteria such as , and were elevated, and decreasing the abundance of the phylum including the genus . An HFS diet induced substantial differences in microbiota composition compared to the fruit-rich diet leading to a lower and a higher abundance as well as reduced abundance of the genus . Compared to a low-fructose diet we observed a decrease of and after the HFS diet. Abundance of positively correlated with plasma cholesterol and LDL level, whereas abundance of was negatively correlated. Different formulations of high-fructose diets induce distinct alterations in gut microbiota composition. High-fructose intake by HFS causes a reduction of beneficial butyrate producing bacteria and a gut microbiota profile that may affect unfavorably host lipid metabolism whereas high consumption of fructose from fruit seems to modulate the composition of the gut microbiota in a beneficial way supporting digestive health and counteracting harmful effects of excessive fructose.
10.3390/nu12113444
Effects of high fructose corn syrup on intestinal microbiota structure and obesity in mice.
Wang Xiaorong,Zhu Liying,Li Xiaoqiong,Wang Xin,Hao Ruirong,Li Jinjun
NPJ science of food
High fructose corn syrup (HFCS)-associated health problems have raised concerns. We investigated the effects of HFCS-containing drinking water on body fat, intestinal microbiota structure of mice, and the relationships between them. HFCS drinking water significantly increased body fat content and altered the intestinal microbiome. The Christensenellaceae R-7 group negatively correlated with body weight, perirenal fat, epididymal fat, and liver fat percentage.
10.1038/s41538-022-00133-7
The small intestine shields the liver from fructose-induced steatosis.
Jang Cholsoon,Wada Shogo,Yang Steven,Gosis Bridget,Zeng Xianfeng,Zhang Zhaoyue,Shen Yihui,Lee Gina,Arany Zoltan,Rabinowitz Joshua D
Nature metabolism
Per capita fructose consumption has increased 100-fold over the last century. Epidemiological studies suggest that excessive fructose consumption, and especially consumption of sweet drinks, is associated with hyperlipidaemia, non-alcoholic fatty liver disease, obesity and diabetes. Fructose metabolism begins with its phosphorylation by the enzyme ketohexokinase (KHK), which exists in two alternatively spliced forms. The more active isozyme, KHK-C, is expressed most strongly in the liver, but also substantially in the small intestine where it drives dietary fructose absorption and conversion into other metabolites before fructose reaches the liver. 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.
10.1038/s42255-020-0222-9
Dietary fructose as a metabolic risk factor.
American journal of physiology. Cell physiology
Over the past decades, the role of the intestinal microbiota in metabolic diseases has come forward. In this regard, both composition and function of our intestinal microbiota is highly variable and influenced by multiple factors, of which diet is one of the major elements. Between 1970 and 1990, diet composition has changed and consumption of dietary sugars has increased, of which fructose intake rose by more than 10-fold. This increased intake of sugars and fructose is considered as one of the major risk factors in the developments of obesity and several metabolic disturbances. In this review, we describe the association of dietary fructose intake with insulin resistance, nonalcoholic fatty liver disease (NAFLD) and lipid metabolism. Moreover, we will focus on the potential causality of this altered gut microbiota using fecal transplantation studies in human metabolic disease and whether fecal microbial transplant can reverse this phenotype.
10.1152/ajpcell.00439.2021
Anti-obesity effect of Lactobacillus rhamnosus LS-8 and Lactobacillus crustorum MN047 on high-fat and high-fructose diet mice base on inflammatory response alleviation and gut microbiota regulation.
Wang Tao,Yan Hong,Lu Yingying,Li Xin,Wang Xin,Shan Yuanyuan,Yi Yanglei,Liu Bianfang,Zhou Yuan,Lü Xin
European journal of nutrition
PURPOSE:The objective of the study was to evaluate the anti-obesity effect of Lactobacillus rhamnosus LS-8 and Lactobacillus crustorum MN047, and illustrate the potential functional mechanism about the alleviation of high fat and high fructose diet (HFFD) induced obesity and related metabolic abnormalities. METHODS:C57BL/6J mice were subjected to a standard or HFFD with or without supplementation of L. rhamnosus LS-8 and L. crustorum MN047 for 10 weeks. Obesity related metabolic indices including glucose tolerance, insulin resistance, serum lipid, liver function, hormones and inflammatory cytokines were assessed by standard protocols. For the monitoring of inflammatory response and lipid metabolism, transcriptional levels were profiled in liver and/or adipose tissues. Furthermore, gut microbiota composition analyses in the fecal samples were performed using 16S rRNA gene sequencing, and gut microbial metabolites, including lipopolysaccharide (LPS) and short-chain fatty acids (SCFAs), were also tested for the assessment of the relationship between gut microbiota variation and inflammatory response. RESULTS:Administration with L. rhamnosus LS-8 and L. crustorum MN047 significantly mitigated body weight gain and insulin resistance, and inflammatory response (TNF-α, IL-1β and IL-6 levels in serum and corresponding mRNA levels in adipose tissues) was significantly inhibited in these two strains-treated mice. Moreover, L. rhamnosus LS-8 and L. crustorum MN047 could partially normalized mRNA expression levels involved in lipid metabolism including Pparγ, Srebp-1c, CD36, Fabp2 and FAS. In addition, these two strains manipulated gut microbiota by decreasing the abundance of Bacteroides and Desulfovibrio and increasing that of Lactobacillus and Bifidobacterium, which in turn raised the levels of feces SCFAs and lowered the levels of circulating LPS. CONCLUSION:These results indicated that L. rhamnosus LS-8 and L. crustorum MN047 supplementation possessed the anti-obesity effect on the HFFD fed mice by alleviating inflammatory response and regulating gut microbiota, which further suggested that these two probiotics can be considered as an alternative dietary supplement in combination with the preventive and therapeutic strategies against obesity and related complications.
10.1007/s00394-019-02117-y
The intestinal-hepatic axis: a comprehensive review on fructose metabolism and its association with mortality and chronic metabolic diseases.
Critical reviews in food science and nutrition
Fructose is a common ingredient of food industry in the form of sucrose and high fructose corn sirup (HFCS). Due to its unique metabolic properties, excessive intake of fructose has been linked to various diseases, including obesity, nonalcoholic fatty liver disease (NAFLD), cardiovascular disease (CVD), chronic renal insufficiency, and even increase the risk of death. Interestingly, although high fructose intake may induce gout, it does not cause hyperuricemia, and the underlying molecular mechanisms remain debated. While previous studies focused on the liver as the primary site of fructose metabolism, recent evidence has suggested a crucial role for the intestine-hepatic axis in fructose metabolism. Low dose fructose is mainly metabolized in the small intestine. Only when the intake exceeds the intestine's metabolic capacity fructose spills over to be metabolized in the liver. High fructose diets also have a significant impact on the diversity of the gut microbiota, leading to alterations in the metabolic byproducts produced by these gut bacteria and thereby inducing endotoxemia. This paper provides a comprehensive review of the epidemiological and pathological studies conducted in recent years, describing the metabolic differences between fructose and glucose and the possible mechanisms underlying the link between excessive fructose intake and chronic metabolic diseases.
10.1080/10408398.2023.2253468
Clitoria ternatea blue petal extract protects against obesity, oxidative stress, and inflammation induced by a high-fat, high-fructose diet in C57BL/6 mice.
Food research international (Ottawa, Ont.)
This study examined the chemical compounds and bioactivity of the aqueous extract of Clitoria ternatea blue petals and investigated its beneficial effects in vivo on a mouse model of obesity and metabolic syndrome. The extract mainly contained flavonoids, and nine compounds were tentatively identified. Male C57BL/6J mice were either fed a standard diet (SD) or a high-fat, high-fructose diet (HFFD) for 16 weeks, and HFFD-fed animals were treated with 0.25%, 0.5%, and 2% (w/w) of the aqueous extract in drinking water. The aqueous extract ameliorated oxidative stress and inflammation mediators. Furthermore, the aqueous extract reduced plasma leptin, free fatty acid, low-density lipoprotein cholesterol levels and hepatic malondialdehyde content. The aqueous extract significantly reduced total cholesterol and ameliorated insulin resistance. The results demonstrated that the aqueous extract of C. ternatea blue petals contains bioactive anthocyanins that exert substantial hypolipidemic and anti-inflammatory effects by promoting reverse cholesterol transport in HFFD-fed mice.
10.1016/j.foodres.2022.112008
High Fructose Corn Syrup Accelerates Kidney Disease and Mortality in Obese Mice with Metabolic Syndrome.
Biomolecules
The presence of obesity and metabolic syndrome is strongly linked with chronic kidney disease (CKD), but the mechanisms responsible for the association are poorly understood. Here, we tested the hypothesis that mice with obesity and metabolic syndrome might have increased susceptibility to CKD from liquid high fructose corn syrup (HFCS) by favoring the absorption and utilization of fructose. We evaluated the pound mouse model of metabolic syndrome to determine if it showed baseline differences in fructose transport and metabolism and whether it was more susceptible to chronic kidney disease when administered HFCS. Pound mice have increased expression of fructose transporter (Glut5) and fructokinase (the limiting enzyme driving fructose metabolism) associated with enhanced fructose absorption. Pound mice receiving HFCS rapidly develop CKD with increased mortality rates associated with intrarenal mitochondria loss and oxidative stress. In pound mice lacking fructokinase, the effect of HFCS to cause CKD and early mortality was aborted, associated with reductions in oxidative stress and fewer mitochondria loss. Obesity and metabolic syndrome show increased susceptibility to fructose-containing sugars and increased risk for CKD and mortality. Lowering added sugar intake may be beneficial in reducing the risk for CKD in subjects with metabolic syndrome.
10.3390/biom13050780
The relationship between excessive dietary fructose consumption and paediatric fatty liver disease.
Pediatric obesity
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.
10.1111/ijpo.12759
Dedicator of Cytokinesis 2 (DOCK2) Deficiency Attenuates Lung Injury Associated with Chronic High-Fat and High-Fructose Diet-Induced Obesity.
The American journal of pathology
Obesity is a major risk factor for lung disease development. However, little is known about the impact of chronic high-fat and high-fructose (HFHF) diet-induced obesity on lung inflammation and subsequent pulmonary fibrosis. Herein we hypothesized that dedicator of cytokinesis 2 (DOCK2) promotes a proinflammatory phenotype of lung fibroblasts (LFs) to elicit lung injury and fibrosis in chronic HFHF diet-induced obesity. An HFHF diet for 20 weeks induced lung inflammation and profibrotic changes in wild-type C57BL/6 mice. CD68 and monocyte chemoattractant protein-1 (MCP-1) expression were notably increased in the lungs of wild-type mice fed an HFHF diet. An HFHF diet further increased lung DOCK2 expression that co-localized with fibroblast-specific protein 1, suggesting a role of DOCK2 in regulating proinflammatory phenotype of LFs. Importantly, DOCK2 knockout protected mice from lung inflammation and fibrosis induced by a HFHF diet. In primary human LFs, tumor necrosis factor-α (TNF-α) and IL-1β induced DOCK2 expression concurrent with MCP-1, IL-6, and matrix metallopeptidase 2. DOCK2 knockdown suppressed TNF-α-induced expression of these molecules and activation of phosphatidylinositol 3-kinase/AKT and NF-κB signaling pathways, suggesting a mechanism of DOCK2-mediated proinflammatory and profibrotic changes in human LFs. Taken together, these findings reveal a previously unrecognized role of DOCK2 in regulating proinflammatory phenotype of LFs, potentiation of lung inflammation, and pulmonary fibrosis in chronic HFHF diet-caused obesity.
10.1016/j.ajpath.2021.10.011
High fructose diet: A risk factor for immune system dysregulation.
Human immunology
Excessive intake of sweets is a predisposing factor for metabolic disorders, and fructose, as one of the major dietary sugars in the diet, has been shown to be a major cause of obesity, diabetes, and metabolic syndrome. These disorders are usually associated with immune dysfunction. Therefore, exploring the effects of a high fructose diet on the immune system may provide insight into the underlying mechanisms of these diseases. We synthesized the available evidence to suggest that excessive fructose intake disrupts the body's immune homeostasis by promoting immune cell metabolic rearrangements, alterations in gut microbial community structure, and intestinal barrier permeability. Indeed, not only does fructose itself affect immune system homeostasis, but its metabolites also have a profound influence. The metabolites from fructolysis are mainly produced in the small intestine and liver and subsequently enter the systemic circulation. Elevated levels of fructose metabolites, such as uric acid, FFAs, and lactate, are closely associated with oxidative stress and local tissue and organ inflammatory responses. In this review, we will focus on the link between fructose and inflammatory responses. In the meanwhile, we will also briefly summarize the studies of cancer development and immune escape mediated by fructose, as it might be beneficial for cancer immunotherapy.
10.1016/j.humimm.2022.03.007
High fructose intake and the route towards cardiometabolic diseases.
Lelis Deborah de Farias,Andrade João Marcus Oliveira,Almenara Camila Cruz Pereira,Broseguini-Filho Gilson B,Mill José Geraldo,Baldo Marcelo Perim
Life sciences
It is known that dietary habits have a strong influence on body metabolism. In the last decades, the dietary habits have changed worldwide, and the consumption of fructose, especially in sugar-sweetened beverages, increased significantly. In this perspective, the present review aimed to summarize the effects of fructose on different cardiometabolic conditions. Clinical, experimental, and epidemiological studies evidenced that fructose can exert several deleterious effects when its consumption is above the recommended amounts. The increased fructose consumption decreases satiety, favoring a positive energy balance, increases adipogenesis, leading to visceral fat accumulation, induces ectopic fat accumulation, especially in the skeletal muscle and liver, leading to insulin resistance, inflammation, and lipid metabolism impairment, increases arterial blood pressure and causes vascular damage. Therefore, increased fructose consumption is linked to the development of alarming cardiometabolic conditions, such as obesity, insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease, and cardiovascular diseases, through several different mechanisms. Further clinical and experimental studies are still necessary to elucidate additional signaling pathways and mechanisms by which fructose is involved in all the mentioned cardiometabolic disorders. Also, the reported findings raise the need for the creation of public health policies aimed to prevent diet-associated cardiometabolic disorders, thus improving the population quality of life.
10.1016/j.lfs.2020.118235
Novel insights in intestinal and hepatic fructose metabolism: from mice to men.
Current opinion in clinical nutrition and metabolic care
PURPOSE OF REVIEW:The rise in fructose consumption in parallel with the current epidemic of obesity and related cardiometabolic disease requires a better understanding of the pathophysiological pathways that are involved. RECENT FINDINGS:Animal studies have shown that fructose has various effects on the intestines that subsequently affect intrahepatic lipid accumulation and inflammation. Fructose adversely affects the gut microbiome - as a producer of endotoxins and intermediates of de novo lipogenesis - and intestinal barrier function. Furthermore, intestinal fructose metabolism shields fructose away from the liver. Finally, fructose 1-phosphate (F1-P) serves as a signal molecule that promotes intestinal cell survival and, consequently, intestinal absorption capacity. Intervention and epidemiological studies have convincingly shown that fructose, particularly derived from sugar-sweetened beverages, stimulates de novo lipogenesis and intrahepatic lipid accumulation in humans. Of interest, individuals with aldolase B deficiency, who accumulate F1-P, are characterized by a greater intrahepatic lipid content. First phase II clinical trials have recently shown that reduction of F1-P, by inhibition of ketohexokinase, reduces intrahepatic lipid content. SUMMARY:Experimental evidence supports current measures to reduce fructose intake, for example by the implementation of a tax on sugar-sweetened beverages, and pharmacological inhibition of fructose metabolism to reduce the global burden of cardiometabolic disease.
10.1097/MCO.0000000000000853
Fructose-mediated effects on gene expression and epigenetic mechanisms associated with NAFLD pathogenesis.
Cellular and molecular life sciences : CMLS
Nonalcoholic fatty liver disease (NAFLD) is a chronic, frequently progressive condition that develops in response to excessive hepatocyte fat accumulation (i.e., steatosis) in the absence of significant alcohol consumption. Liver steatosis develops as a result of imbalanced lipid metabolism, driven largely by increased rates of de novo lipogenesis and hepatic fatty acid uptake and reduced fatty acid oxidation and/or disposal to the circulation. Fructose is a naturally occurring simple sugar, which is most commonly consumed in modern diets in the form of sucrose, a disaccharide comprised of one molecule of fructose covalently bonded with one molecule of glucose. A number of observational and experimental studies have demonstrated detrimental effects of dietary fructose consumption not only on diverse metabolic outcomes such as insulin resistance and obesity, but also on hepatic steatosis and NAFLD-related fibrosis. Despite the compelling evidence that excessive fructose consumption is associated with the presence of NAFLD and may even promote the development and progression of NAFLD to more clinically severe phenotypes, the molecular mechanisms by which fructose elicits effects on dysregulated 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. The aim of this review is to summarize the current research supporting a role for dietary fructose intake in the modulation of transcriptomic and epigenetic mechanisms underlying the pathogenesis of NAFLD.
10.1007/s00018-019-03390-0
High Fructose Intake and Adipogenesis.
International journal of molecular sciences
In modern societies, high fructose intake from sugar-sweetened beverages has contributed to obesity development. In the diet, sucrose and high fructose corn syrup are the main sources of fructose and can be metabolized in the intestine and transported into the systemic circulation. The liver can metabolize around 70% of fructose intake, while the remaining is metabolized by other tissues. Several tissues including adipose tissue express the main fructose transporter GLUT5. In vivo, chronic fructose intake promotes white adipose tissue accumulation through activating adipogenesis. In vitro experiments have also demonstrated that fructose alone induces adipogenesis by several mechanisms, including (1) triglycerides and very-low-density lipoprotein (VLDL) production by fructose metabolism, (2) the stimulation of glucocorticoid activation by increasing 11β-HSD1 activity, and (3) the promotion of reactive oxygen species (ROS) production through uric acid, NOX and XOR expression, mTORC1 signaling and Ang II induction. Moreover, it has been observed that fructose induces adipogenesis through increased ACE2 expression, which promotes high Ang-(1-7) levels, and through the inhibition of the thermogenic program by regulating Sirt1 and UCP1. Finally, microRNAs may also be involved in regulating adipogenesis in high fructose intake conditions. In this paper, we propose further directions for research in fructose participation in adipogenesis.
10.3390/ijms20112787
Dietary Fructose and Fructose-Induced Pathologies.
Annual review of nutrition
The consumption of fructose as sugar and high-fructose corn syrup has markedly increased during the past several decades. This trend coincides with the exponential rise of metabolic diseases, including obesity, nonalcoholic fatty liver disease, cardiovascular disease, and diabetes. While the biochemical pathways of fructose metabolism were elucidated in the early 1990s, organismal-level fructose metabolism and its whole-body pathophysiological impacts have been only recently investigated. In this review, we discuss the history of fructose consumption, biochemical and molecular pathways involved in fructose metabolism in different organs and gut microbiota, the role of fructose in the pathogenesis of metabolic diseases, and the remaining questions to treat such diseases.
10.1146/annurev-nutr-062220-025831
"Sweet death": Fructose as a metabolic toxin that targets the gut-liver axis.
Febbraio Mark A,Karin Michael
Cell metabolism
Glucose and fructose are closely related simple sugars, but fructose has been associated more closely with metabolic disease. Until the 1960s, the major dietary source of fructose was fruit, but subsequently, high-fructose corn syrup (HFCS) became a dominant component of the Western diet. The exponential increase in HFCS consumption correlates with the increased incidence of obesity and type 2 diabetes mellitus, but the mechanistic link between these metabolic diseases and fructose remains tenuous. Although dietary fructose was thought to be metabolized exclusively in the liver, evidence has emerged that it is also metabolized in the small intestine and leads to intestinal epithelial barrier deterioration. Along with the clinical manifestations of hereditary fructose intolerance, these findings suggest that, along with the direct effect of fructose on liver metabolism, the gut-liver axis plays a key role in fructose metabolism and pathology. Here, we summarize recent studies on fructose biology and pathology and discuss new opportunities for prevention and treatment of diseases associated with high-fructose consumption.
10.1016/j.cmet.2021.09.004
High-fructose corn syrup enhances intestinal tumor growth in mice.
Goncalves Marcus D,Lu Changyuan,Tutnauer Jordan,Hartman Travis E,Hwang Seo-Kyoung,Murphy Charles J,Pauli Chantal,Morris Roxanne,Taylor Sam,Bosch Kaitlyn,Yang Sukjin,Wang Yumei,Van Riper Justin,Lekaye H Carl,Roper Jatin,Kim Young,Chen Qiuying,Gross Steven S,Rhee Kyu Y,Cantley Lewis C,Yun Jihye
Science (New York, N.Y.)
Excessive consumption of beverages sweetened with high-fructose corn syrup (HFCS) is associated with obesity and with an increased risk of colorectal cancer. Whether HFCS contributes directly to tumorigenesis is unclear. We investigated the effects of daily oral administration of HFCS in adenomatous polyposis coli (APC) mutant mice, which are predisposed to develop intestinal tumors. The HFCS-treated mice showed a substantial increase in tumor size and tumor grade in the absence of obesity and metabolic syndrome. HFCS increased the concentrations of fructose and glucose in the intestinal lumen and serum, respectively, and the tumors transported both sugars. Within the tumors, fructose was converted to fructose-1-phosphate, leading to activation of glycolysis and increased synthesis of fatty acids that support tumor growth. These mouse studies support the hypothesis that the combination of dietary glucose and fructose, even at a moderate dose, can enhance tumorigenesis.
10.1126/science.aat8515
Dietary fructose improves intestinal cell survival and nutrient absorption.
Nature
Fructose consumption is linked to the rising incidence of obesity and cancer, which are two of the leading causes of morbidity and mortality globally. Dietary fructose metabolism begins at the epithelium of the small intestine, where fructose is transported by glucose transporter type 5 (GLUT5; encoded by SLC2A5) and phosphorylated by ketohexokinase to form fructose 1-phosphate, which accumulates to high levels in the cell. Although this pathway has been implicated in obesity and tumour promotion, the exact mechanism that drives these pathologies in the intestine remains unclear. Here we show that dietary fructose improves the survival of intestinal cells and increases intestinal villus length in several mouse models. The increase in villus length expands the surface area of the gut and increases nutrient absorption and adiposity in mice that are fed a high-fat diet. In hypoxic intestinal cells, fructose 1-phosphate inhibits the M2 isoform of pyruvate kinase to promote cell survival. Genetic ablation of ketohexokinase or stimulation of pyruvate kinase prevents villus elongation and abolishes the nutrient absorption and tumour growth that are induced by feeding mice with high-fructose corn syrup. The ability of fructose to promote cell survival through an allosteric metabolite thus provides additional insights into the excess adiposity generated by a Western diet, and a compelling explanation for the promotion of tumour growth by high-fructose corn syrup.
10.1038/s41586-021-03827-2
Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate.
Nature
Consumption of fructose has risen markedly in recent decades owing to the use of sucrose and high-fructose corn syrup in beverages and processed foods, and this has contributed to increasing rates of obesity and non-alcoholic fatty liver disease. Fructose intake triggers de novo lipogenesis in the liver, in which carbon precursors of acetyl-CoA are converted into fatty acids. The ATP citrate lyase (ACLY) enzyme cleaves cytosolic citrate to generate acetyl-CoA, and is upregulated after consumption of carbohydrates. Clinical trials are currently pursuing the inhibition of ACLY as a treatment for metabolic diseases. However, the route from dietary fructose to hepatic acetyl-CoA and lipids remains unknown. Here, using in vivo isotope tracing, we show that liver-specific deletion of Acly in mice is unable to suppress fructose-induced lipogenesis. Dietary fructose is converted to acetate by the gut microbiota, and this supplies lipogenic acetyl-CoA independently of ACLY. Depletion of the microbiota or silencing of hepatic ACSS2, which generates acetyl-CoA from acetate, potently suppresses the conversion of bolus fructose into hepatic acetyl-CoA and fatty acids. When fructose is consumed more gradually to facilitate its absorption in the small intestine, both citrate cleavage in hepatocytes and microorganism-derived acetate contribute to lipogenesis. By contrast, the lipogenic transcriptional program is activated in response to fructose in a manner that is independent of acetyl-CoA metabolism. These data reveal a two-pronged mechanism that regulates hepatic lipogenesis, in which fructolysis within hepatocytes provides a signal to promote the expression of lipogenic genes, and the generation of microbial acetate feeds lipogenic pools of acetyl-CoA.
10.1038/s41586-020-2101-7
Pathogenesis of Hypertension in Metabolic Syndrome: The Role of Fructose and Salt.
International journal of molecular sciences
Metabolic syndrome is manifested by visceral obesity, hypertension, glucose intolerance, hyperinsulinism, and dyslipidemia. According to the CDC, metabolic syndrome in the US has increased drastically since the 1960s leading to chronic diseases and rising healthcare costs. Hypertension is a key component of metabolic syndrome and is associated with an increase in morbidity and mortality due to stroke, cardiovascular ailments, and kidney disease. The pathogenesis of hypertension in metabolic syndrome, however, remains poorly understood. Metabolic syndrome results primarily from increased caloric intake and decreased physical activity. Epidemiologic studies show that an enhanced consumption of sugars, in the form of fructose and sucrose, correlates with the amplified prevalence of metabolic syndrome. Diets with a high fat content, in conjunction with elevated fructose and salt intake, accelerate the development of metabolic syndrome. This review article discusses the latest literature in the pathogenesis of hypertension in metabolic syndrome, with a specific emphasis on the role of fructose and its stimulatory effect on salt absorption in the small intestine and kidney tubules.
10.3390/ijms24054294
Fructose reprogrammes glutamine-dependent oxidative metabolism to support LPS-induced inflammation.
Nature communications
Fructose intake has increased substantially throughout the developed world and is associated with obesity, type 2 diabetes and non-alcoholic fatty liver disease. Currently, our understanding of the metabolic and mechanistic implications for immune cells, such as monocytes and macrophages, exposed to elevated levels of dietary fructose is limited. Here, we show that fructose reprograms cellular metabolic pathways to favour glutaminolysis and oxidative metabolism, which are required to support increased inflammatory cytokine production in both LPS-treated human monocytes and mouse macrophages. A fructose-dependent increase in mTORC1 activity drives translation of pro-inflammatory cytokines in response to LPS. LPS-stimulated monocytes treated with fructose rely heavily on oxidative metabolism and have reduced flexibility in response to both glycolytic and mitochondrial inhibition, suggesting glycolysis and oxidative metabolism are inextricably coupled in these cells. The physiological implications of fructose exposure are demonstrated in a model of LPS-induced systemic inflammation, with mice exposed to fructose having increased levels of circulating IL-1β after LPS challenge. Taken together, our work underpins a pro-inflammatory role for dietary fructose in LPS-stimulated mononuclear phagocytes which occurs at the expense of metabolic flexibility.
10.1038/s41467-021-21461-4
Health implications of high-fructose intake and current research.
Advances in nutrition (Bethesda, Md.)
Although fructose consumption has dramatically increased and is suspected to be causally linked to metabolic abnormalities, the mechanisms involved are still only partially understood. We discuss the available data and investigate the effects of dietary fructose on risk factors associated with metabolic disorders. The evidence suggests that fructose may be a predisposing cause in the development of insulin resistance in association with the induction of hypertriglyceridemia. Experiments in animals have shown this relation when they are fed diets very high in fructose or sucrose, and human studies also show this relation, although with conflicting results due to the heterogeneity of the studies. The link between increased fructose consumption and increases in uric acid also has been confirmed as a potential risk factor for metabolic syndrome, and insulin resistance/hyperinsulinemia may be causally related to the development of hypertension. Collectively, these results suggest a link between high fructose intake and insulin resistance, although future studies must be of reasonable duration, use defined populations, and improve comparisons regarding the effects of relevant doses of nutrients on specific endpoints to fully understand the effect of fructose intake in the absence of potential confounding factors.
10.3945/an.114.008144
Fructose and high fructose corn syrup: are they a two-edged sword?
Khorshidian Nasim,Shadnoush Mahdi,Zabihzadeh Khajavi Maryam,Sohrabvandi Sara,Yousefi Mojtaba,Mortazavian Amir M
International journal of food sciences and nutrition
High-fructose syrups are used as sugar substitutes due to their physical and functional properties. High fructose corn syrup (HFCS) is used in bakery products, dairy products, breakfast cereals and beverages, but it has been reported that there might be a direct relationship between high fructose intake and adverse health effects such as obesity and the metabolic syndrome. Thus, fructose has recently received much attention, most of which was negative. Although studies have indicated that there might be a correlation between high fructose-rich diet and several adverse effects, however, the results of these studies cannot be certainly generalised to the effects of HFCS; because they have investigated pure fructose at very high concentrations in measurement of metabolic upsets. This review critically considered the advantages and possible disadvantages of HFCS application and consumption in food industry, as a current challenging issue between nutritionists and food technologists.
10.1080/09637486.2020.1862068
Mini review on fructose metabolism.
Akram M,Hamid Abdul
Obesity research & clinical practice
Fructose is a monosaccharide and reducing sugar. It is present in sucrose and honey. Researchers around the world have come together in a just-published study that offers new ideas about how fructose consumption results in obesity and metabolic syndrome, which can lead to diabetes. In this review, we discuss that how fructose causes fatty liver, obesity and insulin resistance. We also discuss the effects of consumption of high fructose corn syrup, dietary fructose, fructose-induced changes in metabolism.:
10.1016/j.orcp.2012.11.002
Copper-Fructose Interactions: A Novel Mechanism in the Pathogenesis of NAFLD.
Nutrients
Compelling epidemiologic data support the critical role of dietary fructose in the epidemic of obesity, metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). The metabolic effects of fructose on the development of metabolic syndrome and NAFLD are not completely understood. High fructose intake impairs copper status, and copper-fructose interactions have been well documented in rats. Altered copper-fructose metabolism leads to exacerbated experimental metabolic syndrome and NAFLD. A growing body of evidence has demonstrated that copper levels are low in NAFLD patients. Moreover, hepatic and serum copper levels are inversely correlated with the severity of NAFLD. Thus, high fructose consumption and low copper availability are considered two important risk factors in NAFLD. However, the causal effect of copper-fructose interactions as well as the effects of fructose intake on copper status remain to be evaluated in humans. The aim of this review is to summarize the role of copper-fructose interactions in the pathogenesis of the metabolic syndrome and discuss the potential underlying mechanisms. This review will shed light on the role of copper homeostasis and high fructose intake and point to copper-fructose interactions as novel mechanisms in the fructose induced NAFLD.
10.3390/nu10111815
Gut microbial adaptation to dietary consumption of fructose, artificial sweeteners and sugar alcohols: implications for host-microbe interactions contributing to obesity.
Payne A N,Chassard C,Lacroix C
Obesity reviews : an official journal of the International Association for the Study of Obesity
The Western diet, comprised of highly refined carbohydrates and fat but reduced complex plant polysaccharides, has been attributed to the prevalence of obesity. A concomitant rise in the consumption of fructose and sugar substitutes such as sugar alcohols, artificial sweeteners, even rare sugars, has mirrored this trend, as both probable contributor and solution to the epidemic. Acknowledgement of the gut microbiota as a factor involved in obesity has sparked much controversy as to the cause and consequence of this relationship. Dietary intakes are a known modulator of gut microbial phylogeny and metabolic activity, frequently exploited to stimulate beneficial bacteria, promoting health benefits. Comparably little research exists on the impact of 'unconscious' dietary modulation on the resident commensal community mediated by increased fructose and sugar substitute consumption. This review highlights mechanisms of potential host and gut microbial fructose and sugar substitute metabolism. Evidence is presented suggesting these sugar compounds, particularly fructose, condition the microbiota, resulting in acquisition of a westernized microbiome with altered metabolic capacity. Disturbances in host-microbe interactions resulting from fructose consumption are also explored.
10.1111/j.1467-789X.2012.01009.x
Integrated omics analysis for characterization of the contribution of high fructose corn syrup to non-alcoholic fatty liver disease in obesity.
Metabolism: clinical and experimental
BACKGROUND:High-Fructose Corn Syrup (HFCS), a sweetener rich in glucose and fructose, is nowadays widely used in beverages and processed foods; its consumption has been correlated to the emergence and progression of Non-Alcoholic Fatty Liver Disease (NAFLD). Nevertheless, the molecular mechanisms by which HFCS impacts hepatic metabolism remain scarce, especially in the context of obesity. Besides, the majority of current studies focuses either on the detrimental role of fructose in hepatic steatosis or compare separately the additive impact of fructose versus glucose in high fat diet-induced NAFLD. AIM:By engaging combined omics approaches, we sought to characterize the role of HFCS in obesity-associated NAFLD and reveal molecular processes, which mediate the exaggeration of steatosis under these conditions. METHODS:Herein, C57BL/6 mice were fed a normal-fat-diet (ND), a high-fat-diet (HFD) or a HFD supplemented with HFCS (HFD-HFCS) and upon examination of their metabolic and NAFLD phenotype, proteomic, lipidomic and metabolomic analyses were conducted to identify HFCS-related molecular alterations of the hepatic metabolic landscape in obesity. RESULTS:Although HFD and HFD-HFCS mice displayed comparable obesity, HFD-HFCS mice showed aggravation of hepatic steatosis, as analysis of the lipid droplet area in liver sections revealed (12,15 % of total section area in HFD vs 22,35 % in HFD-HFCS), increased NAFLD activity score (3,29 in HFD vs 4,86 in HFD-HFCS) and deteriorated hepatic insulin resistance, as compared to the HFD mice. Besides, the hepatic proteome of HFD-HFCS mice was characterized by a marked upregulation of 5 core proteins implicated in de novo lipogenesis (DNL), while an increased phosphatidyl-cholines(PC)/phosphatidyl-ethanolamines(PE) ratio (2.01 in HFD vs 3.04 in HFD-HFCS) was observed in the livers of HFD-HFCS versus HFD mice. Integrated analysis of the omics datasets indicated that Tricarboxylic Acid (TCA) cycle overactivation is likely contributing towards the intensification of steatosis during HFD-HFCS-induced NAFLD. CONCLUSION:Our results imply that HFCS significantly contributes to steatosis aggravation during obesity-related NAFLD, likely deriving from DNL upregulation, accompanied by TCA cycle overactivation and deteriorated hepatic insulin resistance.
10.1016/j.metabol.2023.155552
The Impact of Free Sugar on Human Health-A Narrative Review.
Nutrients
The importance of nutrition in human health has been understood for over a century. However, debate is ongoing regarding the role of added and free sugars in physiological and neurological health. In this narrative review, we have addressed several key issues around this debate and the major health conditions previously associated with sugar. We aim to determine the current evidence regarding the role of free sugars in human health, specifically obesity, diabetes, cardiovascular diseases, cognition, and mood. We also present some predominant theories on mechanisms of action. The findings suggest a negative effect of excessive added sugar consumption on human health and wellbeing. Specific class and source of carbohydrate appears to greatly influence the impact of these macronutrients on health. Further research into individual effects of carbohydrate forms in diverse populations is needed to understand the complex relationship between sugar and health.
10.3390/nu15040889
Oxymatrine relieves high-fructose/fat-induced obesity via reprogramming the activity of lipid metabolism-related enhancer.
Frontiers in endocrinology
Introduction:Emerging evidence demonstrates that the high-fructose and high-fat diet (HFHF) induced obesity and fatty liver disease has become one of the most common metabolic disorders worldwide. Therefore, innovative investigations on compounds targeting obesity and fatty liver diseases are urgently needed. Methods:The high-throughput natural compounds screen was performed to screen the important compounds. A rat HFHF model was constructed, the regulatory function of Oxymatrine in HFHF-induced obesity was further explored. Results:We identified Oxymatrine, a natural compound extracted from , showed a potential compacity in high-fat diet-induced fatty liver disease. We found that oxymatrine significantly inhibited HFHF-induced obesity using a rat HFHF model. Additionally, we found that oxymatrine altered the enhancer landscape of subcutaneous adipose tissues by ChIP-seq analysis using antibodies against the H3K27ac histone modification. Motif enrichment analysis showed the Smad motif was significantly enriched in enhancers altered post-oxymatrine treatment. Further chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) analysis and luciferase reporter assays showed oxymatrine alters the binding of Smad3 on the enhancer regions of B-cell lymphoma 2 (Bcl2) and the enhancer activity of Bcl2. Discussion:Together, our study highlighted oxymatrine could suppress high-fructose and high-fat diet-induced obesity by inhibiting the suppressor of mothers against decapentaplegic 3 (Smad3) binding on obesity-related enhancers.
10.3389/fendo.2023.1145575
The Impact of Excessive Fructose Intake on Adipose Tissue and the Development of Childhood Obesity.
Nutrients
Worldwide, childhood obesity cases continue to rise, and its prevalence is known to increase the risk of non-communicable diseases typically found in adults, such as cardiovascular disease and type 2 diabetes mellitus. Thus, comprehending its multiple causes to build healthier approaches and revert this scenario is urgent. Obesity development is strongly associated with high fructose intake since the excessive consumption of this highly lipogenic sugar leads to white fat accumulation and causes white adipose tissue (WAT) inflammation, oxidative stress, and dysregulated adipokine release. Unfortunately, the global consumption of fructose has increased dramatically in recent years, which is associated with the fact that fructose is not always evident to consumers, as it is commonly added as a sweetener in food and sugar-sweetened beverages (SSB). Therefore, here, we discuss the impact of excessive fructose intake on adipose tissue biology, its contribution to childhood obesity, and current strategies for reducing high fructose and/or free sugar intake. To achieve such reductions, we conclude that it is important that the population has access to reliable information about food ingredients via food labels. Consumers also need scientific education to understand potential health risks to themselves and their children.
10.3390/nu16070939
Perspective: A Historical and Scientific Perspective of Sugar and Its Relation with Obesity and Diabetes.
Advances in nutrition (Bethesda, Md.)
Fructose-containing added sugars, such as sucrose and high-fructose corn syrup, have been experimentally, epidemiologically, and clinically shown to be involved in the current epidemics of obesity and diabetes. Here we track this history of intake of sugar as it relates to these epidemics. Key experimental studies that have identified mechanisms by which fructose causes obesity and diabetes are reviewed, as well as the evidence that the uricase mutation that occurred in the mid-Miocene in ancestral humans acted as a "thrifty gene" that increases our susceptibility for fructose-associated obesity today. We briefly review recent evidence that obesity can also be induced by nondietary sources of fructose, such as from the metabolism of glucose (from high-glycemic carbohydrates) through the polyol pathway. These studies suggest that fructose-induced obesity is driven by engagement of a "fat switch" and provide novel insights into new approaches for the prevention and treatment of these important diseases.
10.3945/an.116.014654
Can fructose influence the development of obesity mediated through hypothalamic alterations?
Cargnin-Carvalho Anderson,de Mello Aline Haas,Bressan Joice Benedet,Backes Kassiane Mathiola,Uberti Marcela Fornari,Fogaça Jéssica Benedet,da Rosa Turatti Cristini,Cavalheiro Eulla Keimili Fernandes Ferreira,Vilela Thais Ceresér,Rezin Gislaine Tezza
Journal of neuroscience research
Epidemiological data from the last decades point to an exponential growth in the number of obese people. Different behavioral factors, mainly associated with food consumption, appear to contribute significantly to its development. Concomitant with increased obesity rates, an increase in the consumption of fructose has been observed; therefore, fructose consumption has been implicated as an important obesogenic factor. However, changes in brain activity due to fructose consumption are possible, especially in relation to hypothalamic satiety mechanisms. In addition, the obese state may provide an environment of chronic inflammation and further contribute to the discontinuation of satiety mechanisms in the hypothalamus. We briefly review the intrinsic alterations to the increased adipose tissue, its connections with the hypothalamus in the control of energy signaling mechanisms and, consequently, the participation of fructose as a co-adjuvant or trigger. Presenting the current context with clinical trials involving human and animal studies, we seek to contribute to a better understanding of the role of fructose in the progression of obesity.
10.1002/jnr.24628
Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity.
The American journal of clinical nutrition
Obesity is a major epidemic, but its causes are still unclear. In this article, we investigate the relation between the intake of high-fructose corn syrup (HFCS) and the development of obesity. We analyzed food consumption patterns by using US Department of Agriculture food consumption tables from 1967 to 2000. The consumption of HFCS increased > 1000% between 1970 and 1990, far exceeding the changes in intake of any other food or food group. HFCS now represents > 40% of caloric sweeteners added to foods and beverages and is the sole caloric sweetener in soft drinks in the United States. Our most conservative estimate of the consumption of HFCS indicates a daily average of 132 kcal for all Americans aged > or = 2 y, and the top 20% of consumers of caloric sweeteners ingest 316 kcal from HFCS/d. The increased use of HFCS in the United States mirrors the rapid increase in obesity. The digestion, absorption, and metabolism of fructose differ from those of glucose. Hepatic metabolism of fructose favors de novo lipogenesis. In addition, unlike glucose, fructose does not stimulate insulin secretion or enhance leptin production. Because insulin and leptin act as key afferent signals in the regulation of food intake and body weight, this suggests that dietary fructose may contribute to increased energy intake and weight gain. Furthermore, calorically sweetened beverages may enhance caloric overconsumption. Thus, the increase in consumption of HFCS has a temporal relation to the epidemic of obesity, and the overconsumption of HFCS in calorically sweetened beverages may play a role in the epidemic of obesity.
10.1093/ajcn/79.4.537
Fructose and hepatic insulin resistance.
Softic Samir,Stanhope Kimber L,Boucher Jeremie,Divanovic Senad,Lanaspa Miguel A,Johnson Richard J,Kahn C Ronald
Critical reviews in clinical laboratory sciences
Excessive caloric intake in a form of high-fat diet (HFD) was long thought to be the major risk factor for development of obesity and its complications, such as fatty liver disease and insulin resistance. Recently, there has been a paradigm shift and more attention is attributed to the effects of sugar-sweetened beverages (SSBs) as one of the culprits of the obesity epidemic. In this review, we present the data invoking fructose intake with development of hepatic insulin resistance in human studies and discuss the pathways by which fructose impairs hepatic insulin action in experimental animal models. First, we described well-characterized pathways by which fructose metabolism indirectly leads to hepatic insulin resistance. These include unequivocal effects of fructose to promote de novo lipogenesis (DNL), impair fatty acid oxidation (FAO), induce endoplasmic reticulum (ER) stress and trigger hepatic inflammation. Additionally, we entertained the hypothesis that fructose can directly impede insulin signaling in the liver. This appears to be mediated by reduced insulin receptor and insulin receptor substrate 2 (IRS2) expression, increased protein-tyrosine phosphatase 1B (PTP1b) activity, whereas knockdown of ketohexokinase (KHK), the rate-limiting enzyme of fructose metabolism, increased insulin sensitivity. In summary, dietary fructose intake strongly promotes hepatic insulin resistance complex interplay of several metabolic pathways, at least some of which are independent of increased weight gain and caloric intake. The current evidence shows that the fructose, but not glucose, component of dietary sugar drives metabolic complications and contradicts the notion that fructose is merely a source of palatable calories that leads to increased weight gain and insulin resistance.
10.1080/10408363.2019.1711360
Tissue-Specific Fructose Metabolism in Obesity and Diabetes.
Current diabetes reports
PURPOSE OF REVIEW:The objective of this review is to provide up-to-date and comprehensive discussion of tissue-specific fructose metabolism in the context of diabetes, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD). RECENT FINDINGS:Increased intake of dietary fructose is a risk factor for a myriad of metabolic complications. Tissue-specific fructose metabolism has not been well delineated in terms of its contribution to detrimental health effects associated with fructose intake. Since inhibitors targeting fructose metabolism are being developed for the management of NAFLD and diabetes, it is essential to recognize how inability of one tissue to metabolize fructose may affect metabolism in the other tissues. The primary sites of fructose metabolism are the liver, intestine, and kidney. Skeletal muscle and adipose tissue can also metabolize a large portion of fructose load, especially in the setting of ketohexokinase deficiency, the rate-limiting enzyme of fructose metabolism. Fructose can also be sensed by the pancreas and the brain, where it can influence essential functions involved in energy homeostasis. Lastly, fructose is metabolized by the testes, red blood cells, and lens of the eye where it may contribute to infertility, advanced glycation end products, and cataracts, respectively. An increase in sugar intake, particularly fructose, has been associated with the development of obesity and its complications. Inhibition of fructose utilization in tissues primary responsible for its metabolism alters consumption in other tissues, which have not been traditionally regarded as important depots of fructose metabolism.
10.1007/s11892-020-01342-8
Molecular aspects of fructose metabolism and metabolic disease.
Cell metabolism
Excessive sugar consumption is increasingly considered as a contributor to the emerging epidemics of obesity and the associated cardiometabolic disease. Sugar is added to the diet in the form of sucrose or high-fructose corn syrup, both of which comprise nearly equal amounts of glucose and fructose. The unique aspects of fructose metabolism and properties of fructose-derived metabolites allow for fructose to serve as a physiological signal of normal dietary sugar consumption. However, when fructose is consumed in excess, these unique properties may contribute to the pathogenesis of cardiometabolic disease. Here, we review the biochemistry, genetics, and physiology of fructose metabolism and consider mechanisms by which excessive fructose consumption may contribute to metabolic disease. Lastly, we consider new therapeutic options for the treatment of metabolic disease based upon this knowledge.
10.1016/j.cmet.2021.09.010