Fructose Consumption Induces Strain-Specific Transcriptomic Response Perturbing Different Pathways in Genetically Diverse Mouse Strains

Metabolic syndrome (MetS) predisposes individuals to type 2 diabetes mellitus and cardiovascular diseases. Epidemiological and clinical studies support fructose intake as an environmental risk for MetS and the associated metabolic diseases. To explore the role of genomic variability in determining metabolic responses to fructose, we fed three strains of mice, namely C57/B6 (B6), DBA and FVB, with 8% fructose for 12 weeks. Fructose-fed DBA mice gained a significantly higher amount of body weight and glucose intolerance from the 4th to the 12thweek, while B6 and FVB showed no differences in these phenotypes over 12 weeks. 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, we applied RNA sequencing to investigate the effect of fructose on the transcriptional profiles of liver, adipose and hypothalamus tissues. Different strains showed distinct patterns of transcriptional and pathway perturbations in a tissue-specific manner. Among pathways altered in the liver tissue, fatty acid and cholesterol metabolic pathways were prominent in B6 mice, while DBA mice showed unique over-representation of pathways related to PPAR signaling pathway. In adipose tissue, pathways are more related to fatty acid metabolism and oxidation in B6 mice, whereas no metabolic pathways were found to be enriched for differential genes in DBA and FVB mice. In hypothalamus tissue, only B6 showed significant enrichment for pathways involved in protein folding, pancreatic secretion and fatty acid beta-oxidation. Using network modeling, we predicted potential key regulators of fructose response such as FGF-21 and Sqle in the liver, Cav1 and DPP-4 in adipose tissue and Fmod in the hypothalamus. Our findings provide molecular insights into the mechanisms by which fructose contributes to the development of MetS and metabolic diseases.