Effects of Voluntary Wheel Running on Markers of NASH During Weight‐Loss in C57Bl/6 Mice

Abstract

Non‐alcoholic steatohepatitis (NASH) is a liver condition characterized as excess lipid accumulation (>7%) and chronic low‐grade inflammation. The pathogenesis of NASH is generalized as multi‐factorial; however, recent evidence proposed a unifocal model in which an imbalance in cholesterol homeostasis is a dominant cause and other co‐factors modify the disease progression. The imbalance in cholesterol homeostasis leads to an accumulation of hepatic cholesterol triggering an inflammatory state subsequently sensitizing the liver to the development of hepatic fibrosis. Central to preventing hepatic fibrosis is bone morphogenic protein and activin membrane bound inhibitor (BAMBI), which inhibits the fibrogenic cascade by serving as pseudoreceptor for the pro‐fibrotic protein, transforming growth factor‐β1 (TGF‐β1). Weight‐loss is central to the management of NASH; however, the therapeutic benefits of exercise during weight‐loss remain unclear as it relates to treating NASH. Therefore, the purpose of this study was to determine if voluntary wheel running (VWR) during weight‐loss improves markers of hepatic steatosis and steatohepatitis versus diet alone in C57Bl/6 mice. Male C57Bl/6 mice were fed a 60% high‐fat diet (HF) for 10 wks to induce obesity. To produce weight loss, HF mice were randomly assigned to a normal diet (ND) either with (WL+VWR) or without (WL) access to running wheels for 8 wks. Age‐matched lean and obese mice were fed a ND and HF, respectively, for 18 wks. At 18 wks, the addition of VWR to weight‐loss resulted in a lower body mass (30.3±0.7 vs. 26.1±0.3 g, p<0.05) than by diet alone; however, HOMA‐IR was not different between WL and WL+VWR, but was 80.5–85.3% (p<0.05) lower than HF. In comparison to HF, WL and WL+VWR had significantly (p<0.05) lower plasma cholesterol (39.8%‐48.1%) and interleukin‐1β (IL‐1β; 46.3–71.6%) concentrations. As expected, WL and WL+VWR resulted in significantly (p<0.05) lower total hepatic lipid (78.8–81.4%) and triglyceride (62.1–77.1%) when compared to HF that was associated with reduced expression of peroxisome proliferator‐activated receptor‐γ (PPARγ; 56.1–71.7%) and CD36 (73.8–80.7%). Interestingly, WL+VWR resulted in significantly (p<0.05) lower hepatic triglyceride (9.6±1.5 vs. 5.8±0.7 mg/mg tissue) and cholesterol (5.3±0.6 vs. 3.2±0.3 mg/mg tissue) when compared to WL. Despite weight‐loss, the toll like receptor 4 (TLR4) mediated intracellular inflammatory signaling cascade remained elevated in both WL and WL+VWR, which was comparable to the HF group. However, WL+VWR had significantly (p<0.05) lower hepatic expression of IL‐1β (65.0–66.3%) and IL‐6 (44.0–58.0%) compared to ND and WL. The lower IL‐1β and IL‐6 hepatic expression may be due in part to a 1.3‐ to 3.8‐fold (p<0.05) greater expression of BAMBI in WL and WL+VWR. In summary, despite significant improvements in circulating and hepatic markers for glucose and lipid metabolism, a transient inflammatory state remained following weight‐loss by diet alone. In contrast, the exercise‐induced increase in hepatic BAMBI and reductions in IL‐1β and IL‐6 during weight‐loss suggests a protective effect of exercise.Support or Funding InformationThis study was supported by the Seed Grants for Translational and Exploratory Projects (J.S.W.) and the Undergraduate Creative Arts and Research Program (K.E.P. and A.S.) at Southern Illinois University Edwardsville.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.