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

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 tissues 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.
Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - Category: Molecular Biology Source Type: research