Nonalcoholic fatty liver disease (NALFD) is characterized as excessive lipid accumulation in the liver in the absence of excessive alcohol consumption. NAFLD is generally considered benign; however, at an undefined threshold, lipid accumulation becomes toxic; i.e., lipotoxic, triggering an inflammatory response progressing to steatohepatitis or nonalcoholic steatohepatitis (NASH). Currently, pharmaceutical interventions provide limited benefits for the treatment of NAFLD and NASH. Lifestyle modifications such as caloric restriction and increasing physical activity to promote weight-loss may provide a more effective therapeutic approach. It remains unclear; however, if a negative caloric balance induced by diet alone or in combination with physical activity is the most effective strategy for reducing hepatic inflammation during weight-loss. Purpose: To determine if weight-loss by caloric restriction when combined with unrestricted physical activity will show lower expression of hepatic inflammation in obese, male C57BL/6 mice when compared to diet alone. Methods: To induce obesity, 8-week old, male C57BL/6 mice were fed a high-fat diet (HFD) (60% kcal from fat) for 10 weeks. An age-matched group of male mice were fed a low-fat diet (LFD) (10% kcal from fat) for the entire 18 weeks of the study, which served as the lean controls. After 10-weeks, mice fed the high-fat diet were randomly assigned to one of three groups for 8-weeks: 1) a high-fat diet , 2) a low-fat diet (DIET) (10% kcal from fat) or 3) a low-fat diet plus ad libitum access to a running wheel (DIET+PA). At the end of the 8 weeks, mice were sacrificed using approved humane methods and plasma and hepatic tissue were collected. Plasma was analyzed for circulating concentrations of total cholesterol, triglycerides, glucose, insulin, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). The degree of insulin resistance was estimated using the vi homeostatic model assessment of insulin resistance (HOMA-IR). Hepatic total lipids, triglycerides, and cholesterol were measured to characterize the degree of lipotoxicity in the tissue. To determine changes in the inflammatory profile of the liver, the expression of hepatic levels of interleukin 1 β(IL-1β), interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), and transforming growth factor-β1 (TGF-β1) mRNA were measured by quantitative RT-PCR. Results: DIET+PA mice had significantly (P<0.05) lower body mass and hepatic triglyceride and cholesterol levels than the LFD, HFD, and DIET groups. The addition of exercise in the DIET+PA group lead to significantly (P<0.05) lower expression of IFN-γ mRNA when compared to HFD mice. These positive changes in hepatic inflammatory profiles were not seen with diet alone. In addition DIET+PA mice had significantly higher expression of IL-6 mRNA and IL-1β in the liver than HFD mice. Conclusion: The addition of exercise to a calorie restrictive diet promoted a reduction of hepatic pro-inflammatory factors and increase of anti-inflammatory factors greater than diet alone. These findings suggest that exercise should be a key component to the prevention and treatment of NAFLD and prevention of NASH.
|Commitee:||Guilford, Brianne, Smith, Bryan|
|School:||Southern Illinois University at Edwardsville|
|Department:||Kinesiology and Health Education|
|School Location:||United States -- Illinois|
|Source:||MAI 56/01M(E), Masters Abstracts International|
|Keywords:||Caloric restriction, Hepatic inflammation, Physical activity|
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