Isocaloric fructose restriction and metabolic improvement in children with obesity and metabolic syndrome.
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ABSTRACT:
SUBMITTER: Lustig RH
PROVIDER: S-EPMC4736733 | biostudies-literature | 2016 Feb
REPOSITORIES: biostudies-literature
Publications
Isocaloric fructose restriction and metabolic improvement in children with obesity and metabolic syndrome.
Lustig Robert H RH Mulligan Kathleen K Noworolski Susan M SM Tai Viva W VW Wen Michael J MJ Erkin-Cakmak Ayca A Gugliucci Alejandro A Schwarz Jean-Marc JM
Obesity (Silver Spring, Md.) 20151026 2
<h4>Objective</h4>Dietary fructose is implicated in metabolic syndrome, but intervention studies are confounded by positive caloric balance, changes in adiposity, or artifactually high amounts. This study determined whether isocaloric substitution of starch for sugar would improve metabolic parameters in Latino (n = 27) and African-American (n = 16) children with obesity and metabolic syndrome.<h4>Methods</h4>Participants consumed a diet for 9 days to deliver comparable percentages of protein, f ...[more]
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Project description:ObjectiveTo investigate the link between dietary sugar consumption and two separate pathogenetic mechanisms associated with metabolic syndrome: de novo lipogenesis (DNL) and nonenzymatic glycation.Design and participantsWe assessed changes in serum d-lactate (the detoxification end-product of methylglyoxal) concentration in response to 9 days of isocaloric fructose restriction in 20 children with obesity and metabolic syndrome, and examined correlations with changes in DNL, liver fat, insulin sensitivity, and other metrics of hepatic metabolism.InterventionsNine days of dietary sugar restriction, with substitution of equal amounts of refined starch.Main outcome measuresOn days 0 and 10, children had laboratory evaluation of d-lactate levels and other analytes, and underwent oral glucose tolerance testing, magnetic resonance spectroscopy to quantify fat depots, and 13C-acetate incorporation into triglyceride (TG) to measure DNL.Resultsd-Lactate was associated with baseline liver fat fraction (P < 0.001) and visceral adipose tissue (P < 0.001) but not with subcutaneous adipose tissue. At baseline, d-lactate was positively correlated with DNL-area under the curve (AUC) (P = 0.003), liver fat fraction (P = 0.02), TG (P = 0.004), and TG/high-density lipoprotein ratio (P = 0.002). After 9 days of isocaloric fructose restriction, serum d-lactate levels reduced by 50% (P < 0.0001), and changes in d-lactate correlated with both changes in DNL-AUC and measures of insulin sensitivity.ConclusionBaseline correlation of d-lactate with DNL and measures of insulin sensitivity and reduction in d-lactate after 9 days of isocaloric fructose restriction suggest that DNL and nonenzymatic glycation are functionally linked via intermediary glycolysis in the pathogenesis of metabolic syndrome and point to fructose as a key dietary substrate that drives both pathways.
| S-EPMC6553815 | biostudies-literature
Project description:We have examined hepatic, genomic, and metabolic responses to dietary protein restriction in the non-pregnant Sprague-Dawley rat. Animals were pair-fed either a 6 or 24% casein-based diet for 7-10 days. At the end of the dietary period, a microarray analysis of the liver was performed, followed by validation of the genes of interest. The rates of appearance of phenylalanine, methionine, serine, and glucose and the contribution of pyruvate to serine and glucose were quantified using tracer methods. Plasma and tissue amino acid levels, enzyme activities, and metabolic intermediates were measured. Protein restriction resulted in significant differential expression of a number of genes involved in cell cycle, cell differentiation, transport, transcription, and metabolic processes. RT-PCR showed that the expression of genes involved in serine biosynthesis and fatty acid oxidation was higher, and those involved in fatty acid synthesis and urea synthesis were lower in the liver of protein-restricted animals. Free serine and glycine levels were higher and taurine levels lower in all tissues examined. Tracer isotope studies showed an ?50% increase in serine de novo synthesis. Pyruvate was the primary (?90%) source of serine in both groups. Transmethylation of methionine was significantly higher in the protein-restricted group. This was associated with a higher S-adenosylmethionine/S-adenosylhomocysteine ratio and lower cystathione ?-synthase and cystathionine ?-lyase activity. Dietary isocaloric protein restriction results in profound changes in hepatic one-carbon metabolism within a short period. These may be related to high methylation demands placed on the organism and caused by possible changes in cellular osmolarity as a result of the efflux of the intracellular taurine.
| S-EPMC3037639 | biostudies-literature
Project description:Consumption of sugar is associated with obesity, type 2 diabetes mellitus, nonalcoholic fatty liver disease, and cardiovascular disease. The conversion of fructose to fat in liver (de novo lipogenesis [DNL]) may be a modifiable pathogenetic pathway. We determined the effect of 9 days of isocaloric fructose restriction on DNL, liver fat, visceral fat (VAT), subcutaneous fat, and insulin kinetics in obese Latino and African American children with habitual high sugar consumption (fructose intake >50 g/d).Children (9-18 years old; n = 41) had all meals provided for 9 days with the same energy and macronutrient composition as their standard diet, but with starch substituted for sugar, yielding a final fructose content of 4% of total kilocalories. Metabolic assessments were performed before and after fructose restriction. Liver fat, VAT, and subcutaneous fat were determined by magnetic resonance spectroscopy and imaging. The fractional DNL area under the curve value was measured using stable isotope tracers and gas chromatography/mass spectrometry. Insulin kinetics were calculated from oral glucose tolerance tests. Paired analyses compared change from day 0 to day 10 within each child.Compared with baseline, on day 10, liver fat decreased from a median of 7.2% (interquartile range [IQR], 2.5%-14.8%) to 3.8% (IQR, 1.7%-15.5%) (P < .001) and VAT decreased from 123 cm3 (IQR, 85-145 cm3) to 110 cm3 (IQR, 84-134 cm3) (P < .001). The DNL area under the curve decreased from 68% (IQR, 46%-83%) to 26% (IQR, 16%-37%) (P < .001). Insulin kinetics improved (P < .001). These changes occurred irrespective of baseline liver fat.Short-term (9 days) isocaloric fructose restriction decreased liver fat, VAT, and DNL, and improved insulin kinetics in children with obesity. These findings support efforts to reduce sugar consumption. ClinicalTrials.gov Number: NCT01200043.
| S-EPMC5813289 | biostudies-literature
Project description:BackgroundCurrently, energy obtained from hypercaloric diets has been part of the obesity and type 2 diabetes mellitus (T2DM) epidemics from childhood to old age. Treatment alternatives have been sought from plants, minerals, and trace elements with metabolic effects. Vanadyl sulfate (VS) has been investigated as a hypoglycemic compound in animal and human studies showing effective insulin-mimetic properties. This characteristic encompasses several molecules that have beneficial pleiotropic effects. The aim was to determine the antiobesity, hypoglycemic, and hypolipidemic effects of VS on fructose-induced metabolic syndrome in aged rats.Material and methodsFive groups of male Wistar rats were made, each with six rats: two groups with normal diet (ND) and three with high-fructose diet (HFD). The first ND group was treated with saline solution (SS), the second with VS; treatment for HFD groups was in the first group with SS, second with VS, and third with metformin. Weight, body mass index (BMI), blood glucose, and lipidic profile were measured; water, food, fructose and energy consumption were also determined. All parameters were compared among groups.Results and discussionAlthough obese rats treated with VS presented anorexia, oligodipsia, and a marked weight loss in the first two weeks. They recovered food and water intake in the third week with a slow recovery of some weight weeks later. VS normalized blood glucose level and decreased triglyceride and insulin levels in obese rats. These results suggest that vanadyl sulfate shows antiobesity, hypoglycemic, and hypolipidemic properties in old obese rats and could be useful as an alternative, additional, and potent preventive treatment for obesity and T2DM control in elderly obese and poorly controlled diabetic patients.ConclusionVS could play an important role in the treatment of metabolic syndrome, contributing to a decrease in obesity and T2DM, through different ways, such as euglycemia, satiety, weight loss, and lipid profile optimization, among others. However, more research is needed to confirm this suggestion.
| S-EPMC6323508 | biostudies-literature
Project description:A fructose-rich diet can induce metabolic syndrome, a combination of health disorders that increases the risk of diabetes and cardiovascular diseases. Diet is also known to alter the microbial composition of the gut, although it is not clear whether such alteration contributes to the development of metabolic syndrome. The aim of this work was to assess the possible link between the gut microbiota and the development of diet-induced metabolic syndrome in a rat model of obesity. Rats were fed either a standard or high-fructose diet. Groups of fructose-fed rats were treated with either antibiotics or faecal samples from control rats by oral gavage. Body composition, plasma metabolic parameters and markers of tissue oxidative stress were measured in all groups. A 16S DNA-sequencing approach was used to evaluate the bacterial composition of the gut of animals under different diets. The fructose-rich diet induced markers of metabolic syndrome, inflammation and oxidative stress, that were all significantly reduced when the animals were treated with antibiotic or faecal samples. The number of members of two bacterial genera, Coprococcus and Ruminococcus, was increased by the fructose-rich diet and reduced by both antibiotic and faecal treatments, pointing to a correlation between their abundance and the development of the metabolic syndrome. Our data indicate that in rats fed a fructose-rich diet the development of metabolic syndrome is directly correlated with variations of the gut content of specific bacterial taxa.
| S-EPMC4526532 | biostudies-literature
Project description:Subjects with obesity frequently have elevated serum vasopressin levels, noted by measuring the stable analog, copeptin. Vasopressin acts primarily to reabsorb water via urinary concentration. However, fat is also a source of metabolic water, raising the possibility that vasopressin might have a role in fat accumulation. Fructose has also been reported to stimulate vasopressin. Here, we tested the hypothesis that fructose-induced metabolic syndrome is mediated by vasopressin. Orally administered fructose, glucose, or high-fructose corn syrup increased vasopressin (copeptin) concentrations and was mediated by fructokinase, an enzyme specific for fructose metabolism. Suppressing vasopressin with hydration both prevented and ameliorated fructose-induced metabolic syndrome. The vasopressin effects were mediated by the vasopressin 1b receptor (V1bR), as V1bR-KO mice were completely protected, whereas V1a-KO mice paradoxically showed worse metabolic syndrome. The mechanism is likely mediated in part by de novo expression of V1bR in the liver that amplifies fructokinase expression in response to fructose. Thus, our studies document a role for vasopressin in water conservation via the accumulation of fat as a source of metabolic water. Clinically, they also suggest that increased water intake may be a beneficial way to both prevent or treat metabolic syndrome.
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Project description:ObjectiveThe risks of excess sugar intake in addition to high-fat diet consumption on immunopathogenesis of obesity-associated metabolic diseases are poorly defined. Interleukin-4 (IL-4) and IL-13 signaling via IL-4Rα regulates adipose tissue lipolysis, insulin sensitivity, and liver fibrosis in obesity. However, the contribution of IL-4Rα to sugar rich diet-driven obesity and metabolic sequelae remains unknown.MethodsWT, IL-4Rα-deficient (IL-4Rα-/-) and STAT6-deficient mice (STAT6-/-) male mice were fed low-fat chow, high fat (HF) or HF plus high carbohydrate (HC/fructose) diet (HF + HC). Analysis included quantification of: (i) body weight, adiposity, energy expenditure, fructose metabolism, fatty acid oxidation/synthesis, glucose dysmetabolism and hepatocellular damage; (ii) the contribution of the hematopoietic or non-hematopoietic IL-4Rα expression; and (iii) the relevance of IL-4Rα downstream canonical STAT6 signaling pathway in this setting.ResultsWe show that IL-4Rα regulated HF + HC diet-driven weight gain, whole body adiposity, adipose tissue inflammatory gene expression, energy expenditure, locomotor activity, glucose metabolism, hepatic steatosis, hepatic inflammatory gene expression and hepatocellular damage. These effects were potentially, and in part, dependent on non-hematopoietic IL-4Rα expression but were independent of direct STAT6 activation. Mechanistically, hepatic ketohexokinase-A and C expression was dependent on IL-4Rα, as it was reduced in IL-4Rα-deficient mice. KHK activity was also affected by HF + HC dietary challenge. Further, reduced expression/activity of KHK in IL-4Rα mice had a significant effect on fatty acid oxidation and fatty acid synthesis pathways.ConclusionOur findings highlight potential contribution of non-hematopoietic IL-4Rα activation of a non-canonical signaling pathway that regulates the HF + HC diet-driven induction of obesity and severity of obesity-associated sequelae.
| S-EPMC8528699 | biostudies-literature
Project description:METABOLIC SYNDROME IS A CLUSTER OF METABOLIC ABNORMALITIES AND IS DEFINED AS THE PRESENCE OF THREE OR MORE OF THE FOLLOWING FACTORS: increased waist circumference, elevated triglycerides, low high-density lipoprotein cholesterol, high blood pressure, and high fasting glucose. Obesity, which is accompanied by metabolic dysregulation often manifested in the metabolic syndrome, is an established risk factor for many cancers. Adipose tissue, particularly visceral fat, is an important metabolic tissue as it secretes systemic factors that alter the immunologic, metabolic, and endocrine milieu and also promotes insulin resistance. Within the growth-promoting, proinflammatory environment of the obese state, cross-talk between macrophages, adipocytes, and epithelial cells occurs via obesity-associated hormones, adipocytokines, and other mediators that may enhance cancer risk and progression. This paper synthesizes the evidence on key molecular mechanisms underlying the obesity-cancer link.
| S-EPMC3530232 | biostudies-literature
Project description:Background and aims: Youth populations with overweight/obesity (OW/OB) exhibit heterogeneity in cardiometabolic health phenotypes (e.g. fasting glucose, serum triglycerides, etc.). The underling mechanisms for those differences are still unclear. This study aimed to analyze the whole blood transcriptome profile (RNA-seq) of children with metabolic healthy overweight/obesity (MHO) and metabolic unhealthy overweight/obesity (MUO) phenotypes. Methods: 27 children with OW/OB (10.14 ± 1.3 years, 59% boys) from the ActiveBrains project were included. MHO was defined as having none of the following criteria for metabolic syndrome: elevated fasting glucose, high serum triglycerides, low high-density lipoprotein cholesterol, and high systolic or diastolic blood pressure, while MUO was defined as presenting one or more of these criteria. Inflammatory markers interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), epidermal growth factor (EGF) and, vascular endothelial growth factor A (VEGF) were additionally determined. Total-blood RNA was analyzed by 5’-end RNA sequencing. Two different bioinformatics approaches were performed: 1) Differential gene expression analyses using Limma R/Bioconductor software package (analyses adjusted by sex and maturational status) and 2) weighted gene coexpression network analyses (WGCNA). Results: Children with MHO had lower values of pro-inflammatory cytokines TNF-α and IL-6 compared to MUO (p < 0.05). 40 genes were differentially expressed (FDR < 0.05) in children with MHO compared to MUO. WGCNA analysis identified 23 gene coexpression modules (i.e. clusters of genes) with low preservation (Zsummary < 2) in children with MHO compared to MUO. Differential and WGCNA gene expression patterns identified 32 genes linked to metabolism, mitochondrial and immune functions. Conclusions: Whole blood transcriptome analysis revealed a distinct pattern of gene expression in children with MHO compared to MUO children. The identified gene expression patterns related to metabolism, mitochondrial and immune functions can promote a better understanding of cardiovascular disease prognosis in individuals with MHO.
2020-11-05 | GSE146869 | GEO
Project description:Increased sugar consumption, especially fructose, is strongly related to the development of type 2 diabetes (T2D) and metabolic syndrome. The aim of this study was to evaluate long term effects of fructose supplementation on Wistar rats. Three-week-old male rats were randomly divided into 2 groups: control (C; n = 14) and fructose fed (FF; n = 18), with a fructose enriched drink (20-25% w/v fructose in water) for 21 weeks. Systolic blood pressure, fasting glycemia, and bodyweight were regularly measured. Glucose tolerance was evaluated three times using an oral glucose tolerance test. Insulin levels were measured concomitantly and insulin resistance markers were evaluated (HOMA 2-IR, Insulin Sensitivity Index for glycemia (ISI-gly)). Lipids profile was evaluated on plasma. This fructose supplementation resulted in the early induction of hypertension without renal failure (stable theoretical creatinine clearance) and in the progressive development of fasting hyperglycemia and insulin resistance (higher HOMA 2-IR, lower ISI-gly) without modification of glucose tolerance. FF rats presented dyslipidemia (higher plasma triglycerides) and early sign of liver malfunction (higher liver weight). Although abdominal fat weight was increased in FF rats, no significant overweight was found. In Wistar rats, 21 weeks of fructose supplementation induced a metabolic syndrome (hypertension, insulin resistance, and dyslipidemia) but not T2D.
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