Differential metabolic and multi-tissue transcriptomic responses to fructose consumption among genetically diverse mice
| Autor: | Yuqi Zhao, Fernando Gomez-Pinilla, Hyae Ran Byun, Le Shu, Jason Hong, Karthick Chella Krishnan, Xia Yang, Montgomery Blencowe, Zhe Ying, Guanglin Zhang |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male FGF21 Adipose tissue Medical Biochemistry and Metabolomics Oral and gastrointestinal Transcriptome chemistry.chemical_compound Mice 0302 clinical medicine 2.1 Biological and endogenous factors Aetiology Adiposity chemistry.chemical_classification 2. Zero hunger 0303 health sciences Liver Disease Fatty liver Personalized nutrition Phenotype Metabolic syndrome 3. Good health Liver Adipose Tissue Mice Inbred DBA Molecular Medicine Type 2 Biotechnology medicine.medical_specialty Biochemistry & Molecular Biology Clinical Sciences 030209 endocrinology & metabolism Fructose Biology Article 03 medical and health sciences Insulin resistance Internal medicine Glucose Intolerance medicine Diabetes Mellitus Genetics Animals Inbred DBA Obesity Molecular Biology Gene Metabolic and endocrine 030304 developmental biology Nutrition Cholesterol Fatty acid medicine.disease Metabolic pathway 030104 developmental biology Endocrinology Diabetes Mellitus Type 2 chemistry Hepatocytes Biochemistry and Cell Biology Insulin Resistance Digestive Diseases 030217 neurology & neurosurgery |
| Zdroj: | Biochimica et biophysica acta. Molecular basis of disease, vol 1866, iss 1 Biochim Biophys Acta Mol Basis Dis |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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