OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) covers a wide spectrum of liver pathology ranging from simple fatty liver to non-alcoholic steatohepatitis (NASH). Notably, immune cell-driven inflammation is a key mechanism in the transition from fatty liver to the more serious NASH. Although exercise training is effective at ameliorating obesity-related diseases, the underlying mechanisms of the beneficial effects of exercise remain unclear. Whether there is an optimal modality and intensity of exercise to treat NAFLD is unknown. The objective of this study was to determine whether high-intensity interval training (HIIT) or moderate-intensity continuous training (MIT) is more effective at ameliorating the progression of NASH.
METHODS: Wildtype mice were fed a high-fat high-carbohydrate (HFHC) diet for 6 weeks and left sedentary (SED) or assigned to either an MIT or HIIT regimen using treadmill running for an additional 16 weeks. MIT and HIIT groups were pair-fed to ensure energy intake was similar between the exercise cohorts. To determine changes in whole-body metabolism, we performed insulin and glucose tolerance tests, indirect calorimetry, and magnetic resonance imaging. NASH progression was determined by triglyceride accumulation, expression of inflammatory genes, and histological assessment of fibrosis. Immune cell populations in the liver were characterized by cytometry by time-of-flight mass spectrometry and progenitor populations within the bone marrow were assessed by flow cytometry. Finally, we analyzed the transcriptional profile of the liver by bulk RNA sequencing.
RESULTS: Compared with SED mice, both HIIT and MIT suppressed weight gain, improved whole-body metabolic parameters, and ameliorated the progression of NASH by reducing hepatic triglyceride levels, inflammation, and fibrosis. However, HIIT was superior to MIT at reducing adiposity, improving whole-body glucose tolerance, and ameliorating liver steatosis, inflammation, and fibrosis, without any changes in body weight. Improved NASH progression in HIIT mice was accompanied by a substantial decrease in the frequency of pro-inflammatory infiltrating monocyte-derived macrophages in the liver and reduced myeloid progenitor populations in the bone marrow. Notably, an acute bout of MIT or HIIT exercise had no effect on the intrahepatic and splenic immune cell populations. In addition, bulk mRNA sequencing of whole liver tissue showed a pattern of gene expression confirming that HIIT was more effective than MIT in improving liver inflammation and lipid biosynthesis.
CONCLUSIONS: Our data suggest that exercise lessens hepatic inflammation during NASH by reducing the accumulation of hepatic monocyte-derived inflammatory macrophages and bone marrow precursor cells. Our findings also indicate that HIIT is superior to MIT in ameliorating the disease in a dietary mouse model of NASH.
Bibliographical noteFunding Information:
This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases ( DK122056 to X.S.R.) and the American Association of Immunologists (Careers in Immunology Fellowship to X.S.R). We recognize the staff from the Research Animal Resources, University Flow Cytometry Resource, Mass Cytometry Facility, Genomics Center, and the Clinical and Translational Science Institute at the University of Minnesota for their assistance. Particularly, we thank Juan Abrahante (Genomics Center) for his contribution to the RNA-sequencing analysis.
© 2021 The Author(s)
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural