Aberrant Regulation of Mitochondrial Biogenesis in Liver of Western Diet Fed Mice following Voluntary Activity

Abstract

The occurrence of liver disease, specifically non-alcoholic fatty liver disease (NAFLD) has risen in the United States in parallel with obesity and Type 2 Diabetes Mellitus. NAFLD can begin is thought perhaps begin with mitochondrial dysfunction, leading to fat accumulation in the liver (steatosis), progressing to cirrhosis and eventually liver failure. The impacts of physical activity on mitochondrial biogenesis in NAFLD are currently unknown. PURPOSE: To determine the effect of Western Diet on liver mitochondrial biogenesis, and if physical activity rescues liver maladaptations associated with Western Diet. METHODS: Eight week old C57BL6/J mice were divided into two groups, normal chow (NC) (54% CHO, 17% fat) and Western Diet (WD) (42% fat, 1.5g cholesterol/kg) and allowed ad libitum consumption of assigned diet for four weeks. After four weeks, animals were further subdivided into Voluntary Wheel Running (VWR) or Sedentary (SED) groups. VWR animals were allowed free access to a running wheel for four weeks. Glucose tolerance tests confirmed diabetes in WD animals. Following diet and activity interventions all animals were euthanized and livers were collected for analysis. Quantitative real-time RT-PCR analysis was used to examine content of genes of mitochondrial biogenesis, specifically Pgc-1α, Pparα, Pparδ and Cox-IV. Data were analyzed by 2X2 ANOVA (diet [NC vs. WD] X activity [SED vs. VWR]) with α set at P<0.05. RESULTS: mRNA content of Pgc-1α was ~50% lower in WD fed animals compared to NC, with no effect of VWR. Pparα was ~2-fold greater in WD fed animals compared to NC, with no effect of VWR. Similar to Pgc-1α, Pparδ mRNA content was ~60% lower in WD compared to NC with no effect of VWR. Cox-IV appeared greater in VWR than SED (p=0.08), which seemed to be driven by NC groups and was unaffected by WD. CONCLUSION: Western Diet appears to hinder the machinery associated with mitochondrial biogenesis, which may lead to liver dysfunction and eventually steatosis. Physical activity does not appear to rescue the maladaptations associated with WD in liver.