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.

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.

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Differential metabolic and multi-tissue transcriptomic responses to fructose consumption among genetically diverse mice.

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Differential metabolic and multi-tissue transcriptomic responses to fructose consumption among genetically diverse mice.

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