Hepatic autophagy has been shown to be regulated by acute exercise and exercise training. Moreover, high‐fat diet‐induced steatosis has been reported to be associated with impaired hepatic autophagy. In addition, autophagy has been shown to be regulated by acute exercise and exercise training in a PGC‐1α dependent manner in skeletal muscle. The aim of this study was to test the hypotheses that high‐fat high‐fructose (HFF) diet changes hepatic autophagy and mitophagy, that exercise training can restore this through a PGC‐1α‐mediated mechanism, and that acute exercise regulates autophagy and mitophagy in the liver. Liver samples were obtained from liver‐specific PGC‐1α KO mice and their littermate Lox/Lox mice fed a HFF diet or a control diet for 13 weeks. The HFF mice were either exercise trained (ExT) on a treadmill the final 5 weeks or remained sedentary (UT). In addition, half of each group performed at the end of the intervention an acute 1 h exercise bout. HFF resulted in increased hepatic BNIP3 dimer and Parkin protein, while exercise training increased BNIP3 total protein without affecting the elevated BNIP3 dimer protein. In addition, exercise training reversed a HFF‐induced increase in hepatic LC3II/LC3I protein ratio, as well as a decreased PGC‐1α mRNA level. Acute exercise increased hepatic PGC‐1α mRNA in HFF UT mice only. In conclusion, this indicates that exercise training in part reverses a HFF‐induced increase in hepatic autophagy and capacity for mitophagy in a PGC‐1α‐independent manner. Moreover, HFF may blunt acute exercise‐induced regulation of hepatic autophagy.

Diet‐induced obesity is associated with hepatic steatosis, which has been linked with activation of the unfolded protein response (UPR). PGC‐1α is a transcriptional coactivator involved in exercise training‐induced adaptations in muscle and liver. Therefore, the aim of this study was to test the hypothesis that PGC‐1α is required for exercise training‐mediated prevention of diet‐induced steatosis and UPR activation in liver. Male liver‐specific PGC‐1α knockout (LKO) and littermate floxed (lox/lox) mice were divided into two groups receiving either control diet (CON) or high‐fat high‐fructose diet (HFF). After 9 weeks, half of the HFF mice were treadmill exercise trained for 4 weeks (HFF+ExT), while the rest were kept sedentary. HFF resulted in increased body and liver weight, adiposity, hepatic steatosis and whole body glucose intolerance as well as decreased hepatic IRE1α phosphorylation. Exercise training prevented the HFF‐induced weight gain and partially prevented increased liver weight, adiposity and glucose intolerance, but with no effect on liver triglycerides. In addition, BiP protein and CHOP mRNA content increased with exercise training compared with CON and HFF, respectively. Lack of PGC‐1α in the liver only resulted in minor changes in the PERK pathway. In conclusion, this study provides evidence for dissociation between diet‐induced hepatic triglyceride accumulation and hepatic UPR activation. In addition, PGC‐1α was not required for maintenance of basal UPR in the liver and due to only minor exercise training effects on UPR further studies are needed to conclude on the potential role of PGC‐1α in exercise training‐induced adaptations in hepatic UPR.