PGC-1α in hepatic UPR during high-fat high-fructose diet and exercise training in mice.

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.

PGC-1α in exercise and fasting-induced regulation of hepatic UPR in mice.

The aim of the present study was to test the hypothesis that PGC-1α is involved in the regulation of hepatic UPR and autophagy in response to both exercise and fasting in mice. Liver-specific PGC-1α knockout (LKO) mice and their floxed littermates (lox/lox) were used in two experimental parts. Liver and plasma were obtained from (1) fed and 18 h fasted mice and (2) immediately after, 2, 6, and 10 h after 1-h treadmill running as well as from resting mice, where one resting group was euthanized at time points corresponding to 0 and 2 h and another corresponding to 6 and 10 h of recovery. Hepatic eIF2α phosphorylation and sXBP1 mRNA content increased immediately after exercise and IRE1α phosphorylation as well as cleaved ATF6 protein content was higher 2 h into recovery than at rest in both genotypes. Fasting reduced hepatic IRE1α phosphorylation and protein content as well as PERK protein and sXBP1 mRNA content similarly in lox/lox and LKO mice. In addition, the hepatic LC3II/LC3I protein ratio increased immediately after exercise and with fasting in both genotypes, while fasting decreased p62 protein content in lox/lox mice. Liver-specific PGC-1α knockout did not affect these responses, but the LC3II/LC3I protein ratio was higher in LKO than lox/lox mice in both rest groups. In conclusion, the present study provides evidence for pathway-specific exercise-induced activation and fasting-induced downregulation of the UPR as well as exercise and fasting-induced regulation of autophagy in mouse liver. In addition, overall PGC-1α does not seem to be required for the fasting and exercise-induced regulation of UPR and autophagy, but may be involved in regulating basal hepatic autophagy.