Role of exercise and rapamycin on the expression of energy metabolism genes in liver tissues of rats fed a high‑fat diet

Abstract

The mTor pathway serves an important role in the development of insulin resistance induced by obesity. exercise improves obesity-associated insulin resistance and hepatic energy metabolism; however, the precise mechanism of this process remains unknown. Therefore, the present study investigated the role of rapamycin, an inhibitor of mTor, on exercise-induced expression of hepatic energy metabolism genes in rats fed a high-fat diet (HFd). a total of 30 male rats were divided into the following groups: normal group (n=6) fed chow diets and HFd group (n=24) fed an HFd for 6 weeks. The HFd rats performed exercise adaptation for 1 week and were randomly divided into the four following groups (each containing six rats): i) Group of HFd rats with sedentary (H group); ii) group of HFd rats with exercise (He group); iii) group of HFd rats with rapamycin (Hr group); and iv) group of HFd rats with exercise and rapamycin (Her group). Both He and Her rats were placed on incremental treadmill training for 4 weeks (from week 8-11). Both Hr and Her rats were injected with rapamycin intraperitoneally at the dose of 2 mg/kg once a day for 2 weeks (from week 10-11). all rats were sacrificed following a 12-16 h fasting period at the end of week 11. The levels of mitochondrial and oxidative enzyme activities, as well as of the expression of genes involved in energy metabolism were assessed in liver tissues. Biochemical assays and oil red staining were used to assess the content of hepatic triglycerides (TGs). The results indicated that exercise, but not rapamycin, reduced TG content in the liver of HFd rats. Further analysis indicated that rapamycin reduced the activity of cytochrome c oxidase, but not the activities of succinate dehydrogenase and β-hydroxyacyl-coa dehydrogenase in the liver of HFD rats. Exercise significantly upregulated the mrna expression of peroxisome proliferator-activated receptor γ coactivator 1 β, while rapamycin exhibited no effect on the mrna expression levels of hepatic transcription factors associated with energy metabolism enzymes in the liver of HFd rats. collectively, the results indicated that exercise reduced TG content and upregulated mitochondrial metabolic gene expression in the liver of HFd rats. Moreover, this mechanism may not involve the mTor pathway.

Hepatic transcriptional responses to fasting and feeding

“…Additionally, exercise has been suggested to decrease hepatic oxidative stress (Hu et al 2013) and to decrease HFD-induced NF-κB activation and proinflammatory cytokine production (Gehrke et al 2019). These beneficial effects of exercise on lipid metabolism appear to be independent of the mTOR pathway (Tu et al 2020) and potentially mediated by increased PPARαstimulated fat oxidation (Alex et al 2015).…”

Exercise, mTOR Activation, and Potential Impacts on the Liver in Rodents

“…Tu et al (2020) [ 8 ] investigated the effects of four weeks of treadmill exercise and the administration of rapamycin on energy metabolism gene expression in the hepatic tissue of rats previously supplemented with a high-fat diet (HFD). The authors found lower levels of phosphorylated S6K1, a marker of mTORC1 pathway activity, and reduced hepatic triglyceride content in response to the exercise protocol.…”

“…Indeed, other important genes were not investigated, such as PPARγ (peroxisome proliferator-activated receptor gamma) and FABP4 (fatty acid binding protein 4). Moreover, Akt phosphorylation has been related to mTORC2 signaling, and it was not modified by the exercise protocol [ 8 ]. Guarino et al (2020) [ 99 ] found higher phosphorylation of AMPK, followed by lower S6K1 expression and hepatic triglycerides levels in mice with non-alcoholic steatohepatitis.…”

“…Resistance exercise training results in higher protein expression of sqstm1/p62 (sequestosome 1), a peptide involved in the autophagy process within the liver [ 7 ]. In addition, exercise results in greater mRNA expression of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1), which is an inducible co-regulator of nuclear receptors involved in a wide variety of biological responses, such as glucose and lipid metabolism, as well as in reducing triacylglycerol levels in the liver and plasmatic glycemia in diet-induced obese rats [ 8 ]. Similarly, other authors have observed a reduction in hepatic triacylglycerol levels accompanied by insulin metabolism improvements in response to a 4-week voluntary running intervention in an experimental model submitted to a high-fat diet [ 9 ].…”