Kelty, T. J.; Franczak, E.; Gay, N. R.; Many, G. M.; Sagendorf, T. J.; Sanford, J. A.; Hou, Z.; Gaul, D. A.; Fernandez, F.; Burant, C.; Hevener, A. L.; Adkins, J. N.; Bodine, S.; Lindholm, M. E.; Ortlund, E. A.; Schenk, S.; Thyfault, J. P.; Rector, R. S.; MoTrPAC Research Group,

The mechanisms by which exercise modulate liver metabolism, a central regulator of systemic metabolism, are poorly understood. Leveraging data from MoTrPAC, we analyzed liver adaptations across 1, 2, 4, and 8 weeks of exercise in male and female rats using multi-omic approaches. Female livers displayed a progressive increase in oxidative phosphorylation (OXPHOS) complexes (at the protein level), while male livers showed an increase in acetylation of OXPHOS, TCA cycle, and fatty acid oxidation enzymes. Exercise also enhanced liver cholesterol and bile acid synthesis, reducing liver lipid metabolites in males after 8 weeks of exercise. Male rats had higher fecal cholesterol and cholic acid levels, indicating a sex-specific mechanism of lipid excretion with exercise. Moreover, 8 weeks of training reduced markers related to hepatic stellate cell activation and fibrosis in both sexes. This study highlights the sexual dimorphic and temporal molecular signatures by which exercise modulates liver metabolism to provide hepatoprotective effects.