Chronic stress alters hepatic metabolism and thermodynamic respiratory efficiency affecting epigenetics in C57BL/6 mice

Aleksandra Nikolic; Pia Fahlbusch; Nele-Kathrien Riffelmann; Natalie Wahlers; Sylvia Jacob; Sonja Hartwig; Ulrike Kettel; Martina Schiller; Matthias Dille; Hadi Al-Hasani; Jörg Kotzka; Birgit Knebel

doi:10.1016/j.isci.2024.109276

Chronic stress alters hepatic metabolism and thermodynamic respiratory efficiency affecting epigenetics in C57BL/6 mice

iScience. 2024 Feb 20;27(3):109276. doi: 10.1016/j.isci.2024.109276. eCollection 2024 Mar 15.

Authors

Aleksandra Nikolic^{1

2}, Pia Fahlbusch^{1

2}, Nele-Kathrien Riffelmann¹, Natalie Wahlers¹, Sylvia Jacob¹, Sonja Hartwig^{1

2}, Ulrike Kettel¹, Martina Schiller¹, Matthias Dille¹, Hadi Al-Hasani^{1

2

3}, Jörg Kotzka^{1

2}, Birgit Knebel^{1

2}

Affiliations

¹ Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center at the Heinrich-Heine-University Duesseldorf, Leibniz Center for Diabetes Research, 40225 Duesseldorf, Germany.
² German Center for Diabetes Research (DZD), Partner Duesseldorf, 40225 Duesseldorf, Germany.
³ Medical Faculty Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany.

Abstract

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 β-oxidation, correlating with EE. After Cvs, mitochondrial function revealed increased thermodynamic efficiency (ƞ-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.

Keywords: Cell biology; Epigenetics; Molecular biology; Physiology; Transcriptomics.