Long-term metabolic effect of chronic variable stress on liver function and the role of FGF21

Chronic stress disorders lead to metabolic complications, including hepatic lipid accumulation. Here we address the role of FGF21 in the hepatic metabolic regulation in a mouse model for chronic variable stress (Cvs). Global FGF21KO and WT mice show an intact stress response with short-term Cvs induced alterations in hepatic lipid metabolism, mitochondrial function and gene expression. Hepatic steatosis is found with the highest significance in enrichment analyses of hepatic transcriptome data, with PPARa and SREBP-1 as main upstream regulatory molecules, which are directly associated to FGF21. After 3 months recovery, stress-related metabolic improvements are not visible in FGF21KO mice in contrast to WT mice, indicating the crucial role of FGF21 in the post-stress metabolic adaptations. Overall, we suggest that Cvs-induced gene regulation determines the metabolic late effects after stress. Furthermore, FGF21 is a key player in the protection from stress-induced hepatic lipid accumulation. Wildtype (WT; FGF21+/+) and Fgf21 knockout (FGF21KO; FGF21-/-) (doi:https://doi:10.1210/en.2009-0119) 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 genotype. Mice were phenotyped for body composition, serum analyses, physiological tolerance tests and mitochondrial function, both immediately after stress and after 3 month recovery to determine longitudinal metabolic stress adaptation and the role of FGF21 in this context.