Chronic stress alters hepatic metabolism and thermodynamic respiratory efficiency affecting epigenetics in C57BL/6 mice [MeDIP-seq]
Chronic stress episodes increase metabolic disease risk even after recovery. We propose that persistent stress detrimentally impacts hepatic metabolic reprogramming, particularly mitochondrial function. In male C57BL/6 mice chronic variable stress (Cvs) reduced energy expenditure (EE) and body mass despite increased energy intake versus controls. This coincided with decreased glucose metabolism and increased lipid ß-oxidation, correlating with EE. After Cvs, mitochondrial function revealed increased thermodynamic efficiency (?-opt) of complex CI, positively correlating with blood glucose and NEFA and inversely with EE. After Cvs recovery, the metabolic flexibility of hepatocytes was lost. Reduced CI-driving NAD+/NADH ratio, and diminished methylation-related one-carbon cycle components hinted at epigenetic regulation. Although initial DNA methylation differences were minimal after Cvs, they diverged during the recovery phase. Here, the altered enrichment of mitochondrial DNA methylation and linked transcriptional networks were observed. In conclusion, Cvs rapidly initiates the reprogramming of hepatic energy metabolism, supported by lasting epigenetic modifications. Overall design: C57/Bl6 male mice were stressed with our Cvs protocol as previously described (doi:https://doi.org/10.1016/j.molmet.2018.06.012), or left untreated (Ctrl). Transcriptome analyses (MTA array, Affymetrix) was performed in Ctrl and Cvs liver biopsies of each condition. Mice were phenotyped for body composition, serum analyses, methylome,  mitochondrial proteome and mitochondrial function and thermodymamic efficency immediately after stress to determine CVS dependant molecular alterations im metabolic regulation.