RT Journal Article
SR Electronic
T1 Differential Metabolic and Multi-tissue Transcriptomic Responses to Fructose Consumption among Genetically Diverse Mice
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 439562
DO 10.1101/439562
A1 Guanglin Zhang
A1 Hyae Ran Byun
A1 Zhe Ying
A1 Montgomery Blencowe
A1 Yuqi Zhao
A1 Jason Hong
A1 Le Shu
A1 Karthick Chella Krishnan
A1 Fernando Gomez-Pinilla
A1 Xia Yang
YR 2019
UL http://biorxiv.org/content/early/2019/04/24/439562.abstract
AB High fructose intake is a major risk for metabolic syndrome; however, its effects seem to vary across individuals. To determine main factors involved in the inter-individual responses to fructose, we fed inbred mouse strains C57BL/6J (B6), DBA/2J (DBA) and FVB/NJ (FVB) with fructose. DBA mice showed the highest susceptibility to gain adiposity and glucose intolerance. Elevated insulin was found in DBA and FVB mice, and cholesterol levels were uniquely elevated in B6 mice. The transcriptional profiles of liver, hypothalamus, and adipose tissues showed strain- and tissue-specific pathways altered by fructose, such as fatty acid and cholesterol pathways for B6 and PPAR signaling for DBA in liver, and oxidative phosphorylation for B6 and protein processing for DBA in hypothalamus. Using network modeling, we predicted potential strain-specific key regulators of fructose response such as Fgf21 (DBA) and Lss (B6) in liver, and validated strain-biased responses as well as the regulatory actions of Fgf21 and Lss in primary hepatocytes. Our findings support that fructose perturbs individualized tissue networks and pathways and associates with distinct features of metabolic dysfunctions across genetically diverse mice. Our results elucidate the molecular pathways and gene regulatory mechanisms underlying inter-individual variability in response to high fructose diet.