Treadmill Exercise Improves Nonalcoholic Fatty Liver Disease in db/db Mice by Up-Regulating FNDC5 through p38MAPK Signaling Pathway

The aim of this paper was to investigate the role and molecular mechanism of 8-week exercise in improving NAFLD (nonalcoholic fatty liver disease) in type II diabetic mice. Eight-week-old male m/m at SPF level as control group (Con group), and eight-week-old male db/db mice at SPF level were randomly divided into four groups: type II diabetic model group (db group), type II diabetic exercise group (db+EX group), type II diabetic exercise combined with p38MAPK inhibitor group (db+EX+SB203580 group), and p38MAPK inhibitor group (db+SB203580 group), every group has 10 mice. Exercise intervention was performed 2 h after intraperitoneal injection of p38MAPK inhibitor, and the exercise intervention was performed for 40 minutes every day, 5 days every week for 8 weeks. The intervention effects of exercise intervention on NAFLD were evaluated by body weight, blood glucose, liver-to-body ratio, lipids, and HE, oil red and Masson staining in mice. The related protein and mRNA expression levels were determined by Western blot and qRT-PCR. The results showed that 8 weeks of exercising significantly reduced the increase in body weight, blood glucose, and liver-to-body ratio and decreased blood lipid levels in db/db mice. Exercise intervention reduced hepatic steatosis, collagen deposition and the expression levels of ACC1 and SREBF1 in mice. The p38MAPK inhibitor intervention exacerbated hepatic steatosis and collagen deposition, while exercise combined with p38 inhibitor did not have a synergistic effect. Exercise upregulated the protein expression levels of FNDC5 in mouse liver and muscle and also increased the FNDC5 mRNA expression levels in mouse liver compared to the db model group. Exercise also decreased the expression of pro-apoptotic proteins BAX, Caspase8 and Caspase9 and increased the expression of anti-apoptotic protein BCL2 in db/db mice. In addition, the p38 inhibitor group decreased not only the expression of p-p38 protein in the liver of db/db mice, but also decreased the expression of FNDC5 protein in the liver and gastrocnemius muscle of db/db mice, which subsequently led to excessive apoptosis. Exercise combined with p38 inhibitor intervention reduced p-p38 protein expression, but did not significantly alter FNDC5 and apoptosis-related proteins. The above results suggest that 8 weeks of treadmill exercise can effectively alleviate NAFLD in type II diabetic mice, and the mechanism may be through the p38MAPK-dependent pathway to upregulate FNDC5 expression, reducing liver fibrosis, and attenuate apoptosis in mouse hepatocytes

CSTR: 32200.14.cjcb.2023.01.0003