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Project description:Understanding how individuals react differently to the same treatment is a major concern in precision medicine. Metabolic challenges such as the one posed by high fructose intake are important determinants of disease mechanisms. We embarked on studies to determine how fructose affects differential metabolic dysfunctions across genetically dissimilar mice, namely, C57BL/6?J (B6), DBA/2?J (DBA) and FVB/NJ (FVB), by integrating physiological and gene regulatory mechanisms. We report that fructose has strain-specific effects, involving tissue-specific gene regulatory cascades in hypothalamus, liver, and white adipose tissues. DBA mice showed the largest numbers of genes associated with adiposity, congruent with their highest susceptibility to adiposity gain and glucose intolerance across the three tissues. In contrast, B6 and FVB mainly exhibited cholesterol phenotypes, accompanying the largest number of adipose genes correlating with total cholesterol in B6, and liver genes correlating with LDL in FVB mice. Tissue-specific network modeling predicted strain-and tissue-specific regulators such as Fgf21 (DBA) and Lss (B6), which were subsequently validated in primary hepatocytes. Strain-specific fructose-responsive genes revealed susceptibility for human diseases such that genes in liver and adipose tissue in DBA showed strong enrichment for human type 2 diabetes and obesity traits. Liver and adipose genes in FVB were mostly related to lipid traits, and liver and adipose genes in B6 showed relevance to most cardiometabolic traits tested. Our results show that fructose induces gene regulatory pathways that are tissue specific and dependent on the genetic make-up, which may underlie interindividual variability in cardiometabolic responses to high fructose consumption.
| S-EPMC6993985 | biostudies-literature
Project description:The escalating prevalence of metabolic syndrome (MetS) poses significant risks to type 2 diabetes mellitus, cardiovascular diseases, and non-alcoholic fatty liver disease. High fructose intake has emerged as an environmental risk for MetS and the associated metabolic diseases. To examine inter-individual variability in MetS susceptibility in response to fructose consumption, here we fed three inbred mouse strains, namely C57BL/6J (B6), DBA (DBA) and FVB/NJ (FVB) with 8% fructose in drinking water for 12 weeks. We found that fructose-fed DBA mice had significantly higher amount of body weight, adiposity, and glucose intolerance starting from the 4th week of fructose feeding compared to the control group, while B6 and FVB showed no differences in these phenotypes over the course of fructose feeding. In addition, elevated insulin levels were found in fructose-fed DBA and FVB mice, and cholesterol levels were uniquely elevated in B6 mice. To explore the molecular underpinnings of the observed distinct phenotypic responses among strains, we applied RNA sequencing to investigate the effect of fructose on the transcriptional profiles of liver and hypothalamus tissues, revealing strain- and tissue-specific patterns of transcriptional and pathway perturbations. Strain-specific liver pathways altered by fructose include fatty acid and cholesterol metabolic pathways for B6 and PPAR signaling for DBA. In hypothalamus tissue, only B6 showed significantly enriched pathways such as protein folding, pancreatic secretion, and fatty acid beta-oxidation. Using network modeling, we predicted potential strain-specific key regulators of fructose response such as Fgf21 (DBA) and Lss (B6) in liver, and Fmod (B6) in hypothalamus. We validated strain-biased responses of Fgf21 and Lss to fructose in primary hepatocytes. Our findings support that fructose perturbs different tissue networks and pathways in genetically diverse mice and associates with distinct features of metabolic dysfunctions. These results highlight individualized molecular and metabolic responses to fructose consumption and may help guide the development of personalized strategies against fructose-induced MetS.
2019-12-03 | GSE123894 | GEO
Project description:The escalating prevalence of metabolic syndrome (MetS) poses significant risks to type 2 diabetes mellitus, cardiovascular diseases, and non-alcoholic fatty liver disease. High fructose intake has emerged as an environmental risk for MetS and the associated metabolic diseases. To examine inter-individual variability in MetS susceptibility in response to fructose consumption, here we fed three inbred mouse strains, namely C57BL/6J (B6), DBA (DBA) and FVB/NJ (FVB) with 8% fructose in drinking water for 12 weeks. We found that fructose-fed DBA mice had significantly higher amount of body weight, adiposity, and glucose intolerance starting from the 4th week of fructose feeding compared to the control group, while B6 and FVB showed no differences in these phenotypes over the course of fructose feeding. In addition, elevated insulin levels were found in fructose-fed DBA and FVB mice, and cholesterol levels were uniquely elevated in B6 mice. To explore the molecular underpinnings of the observed distinct phenotypic responses among strains, we applied RNA sequencing to investigate the effect of fructose on the transcriptional profiles of liver and hypothalamus tissues, revealing strain- and tissue-specific patterns of transcriptional and pathway perturbations. Strain-specific liver pathways altered by fructose include fatty acid and cholesterol metabolic pathways for B6 and PPAR signaling for DBA. In hypothalamus tissue, only B6 showed significantly enriched pathways such as protein folding, pancreatic secretion, and fatty acid beta-oxidation. Using network modeling, we predicted potential strain-specific key regulators of fructose response such as Fgf21 (DBA) and Lss (B6) in liver, and Fmod (B6) in hypothalamus. We validated strain-biased responses of Fgf21 and Lss to fructose in primary hepatocytes. Our findings support that fructose perturbs different tissue networks and pathways in genetically diverse mice and associates with distinct features of metabolic dysfunctions. These results highlight individualized molecular and metabolic responses to fructose consumption and may help guide the development of personalized strategies against fructose-induced MetS.
2019-12-03 | GSE123893 | GEO
Project description:The escalating prevalence of metabolic syndrome (MetS) poses significant risks to type 2 diabetes mellitus, cardiovascular diseases, and non-alcoholic fatty liver disease. High fructose intake has emerged as an environmental risk for MetS and the associated metabolic diseases. To examine inter-individual variability in MetS susceptibility in response to fructose consumption, here we fed three inbred mouse strains, namely C57BL/6J (B6), DBA (DBA) and FVB/NJ (FVB) with 8% fructose in drinking water for 12 weeks. We found that fructose-fed DBA mice had significantly higher amount of body weight, adiposity, and glucose intolerance starting from the 4th week of fructose feeding compared to the control group, while B6 and FVB showed no differences in these phenotypes over the course of fructose feeding. In addition, elevated insulin levels were found in fructose-fed DBA and FVB mice, and cholesterol levels were uniquely elevated in B6 mice. To explore the molecular underpinnings of the observed distinct phenotypic responses among strains, we applied RNA sequencing to investigate the effect of fructose on the transcriptional profiles of liver and hypothalamus tissues, revealing strain- and tissue-specific patterns of transcriptional and pathway perturbations. Strain-specific liver pathways altered by fructose include fatty acid and cholesterol metabolic pathways for B6 and PPAR signaling for DBA. In hypothalamus tissue, only B6 showed significantly enriched pathways such as protein folding, pancreatic secretion, and fatty acid beta-oxidation. Using network modeling, we predicted potential strain-specific key regulators of fructose response such as Fgf21 (DBA) and Lss (B6) in liver, and Fmod (B6) in hypothalamus. We validated strain-biased responses of Fgf21 and Lss to fructose in primary hepatocytes. Our findings support that fructose perturbs different tissue networks and pathways in genetically diverse mice and associates with distinct features of metabolic dysfunctions. These results highlight individualized molecular and metabolic responses to fructose consumption and may help guide the development of personalized strategies against fructose-induced MetS.
2019-12-03 | GSE123875 | GEO
Project description:Differential Metabolic and Multi-tissue Transcriptomic Responses to Fructose Consumption among Genetically Diverse Mice
| PRJNA510134 | ENA
Project description:Differential Metabolic and Multi-tissue Transcriptomic Responses to Fructose Consumption among Genetically Diverse Mice [Adipose]
| PRJNA510125 | ENA
Project description:Differential Metabolic and Multi-tissue Transcriptomic Responses to Fructose Consumption among Genetically Diverse Mice [Hypothalamus]
| PRJNA510129 | ENA
Project description:Differential Metabolic and Multi-tissue Transcriptomic Responses to Fructose Consumption among Genetically Diverse Mice [Liver]
| PRJNA510133 | ENA
Project description:BackgroundIt is unclear how high fructose consumption induces disparate metabolic responses in genetically diverse mouse strains.ObjectiveWe aimed to investigate whether the gut microbiota contributes to differential metabolic responses to fructose.MethodsEight-week-old male C57BL/6J (B6), DBA/2J (DBA), and FVB/NJ (FVB) mice were given 8% fructose solution or regular water (control) for 12 wk. The gut microbiota composition in cecum and feces was analyzed using 16S ribosomal DNA sequencing, and permutational multivariate ANOVA (PERMANOVA) was used to compare community across mouse strains, treatments, and time points. Microbiota abundance was correlated with metabolic phenotypes and host gene expression in hypothalamus, liver, and adipose tissues using Biweight midcorrelation. To test the causal role of the gut microbiota in determining fructose response, we conducted fecal transplants from B6 to DBA mice and vice versa for 4 wk, as well as gavaged antibiotic-treated DBA mice with Akkermansia for 9 wk, accompanied with or without fructose treatment.ResultsCompared with B6 and FVB, DBA mice had significantly higher Firmicutes to Bacteroidetes ratio and lower baseline abundance of Akkermansia and S24-7 (P < 0.05), accompanied by metabolic dysregulation after fructose consumption. Fructose altered specific microbial taxa in individual mouse strains, such as a 7.27-fold increase in Akkermansia in B6 and 0.374-fold change in Rikenellaceae in DBA (false discovery rate <5%), which demonstrated strain-specific correlations with host metabolic and transcriptomic phenotypes. Fecal transplant experiments indicated that B6 microbes conferred resistance to fructose-induced weight gain in DBA mice (F = 43.1, P < 0.001), and Akkermansia colonization abrogated the fructose-induced weight gain (F = 17.8, P < 0.001) and glycemic dysfunctions (F = 11.8, P = 0.004) in DBA mice.ConclusionsOur findings support that differential microbiota composition between mouse strains is partially responsible for host metabolic sensitivity to fructose, and that Akkermansia is a key bacterium that confers resistance to fructose-induced metabolic dysregulation.
| S-EPMC7549307 | biostudies-literature
Project description:Adropin is a peptide hormone encoded by the Energy Homeostasis Associated (ENHO) gene whose physiological role in humans remains incompletely defined. Here we investigated the impact of dietary interventions that affect systemic glucose and lipid metabolism on plasma adropin concentrations in humans. Consumption of glucose or fructose as 25% of daily energy requirements (E) differentially affected plasma adropin concentrations (P < 0.005) irrespective of duration, sex or age. Glucose consumption reduced plasma adropin from 3.55 ± 0.26 to 3.28 ± 0.23 ng/ml (N = 42). Fructose consumption increased plasma adropin from 3.63 ± 0.29 to 3.93 ± 0.34 ng/ml (N = 45). Consumption of high fructose corn syrup (HFCS) as 25% E had no effect (3.43 ± 0.32 versus 3.39 ± 0.24 ng/ml, N = 26). Overall, the effect of glucose, HFCS and fructose on circulating adropin concentrations were similar to those observed on postprandial plasma triglyceride concentrations. Furthermore, increases in plasma adropin levels with fructose intake were most robust in individuals exhibiting hypertriglyceridemia. Individuals with low plasma adropin concentrations also exhibited rapid increases in plasma levels following consumption of breakfasts supplemented with lipids. These are the first results linking plasma adropin levels with dietary sugar intake in humans, with the impact of fructose consumption linked to systemic triglyceride metabolism. In addition, dietary fat intake may also increase circulating adropin concentrations.
| S-EPMC4592955 | biostudies-literature