Effects Of Endurance Exercise On Non-alcoholic Fatty Liver Disease And Type 2 Diabetes Mellitus

PURPOSE: Non-Alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases. Although no cure is available, regular endurance exercise (EXE) has emerged as an effective non-pharmacological strategy. However, its molecular mechanisms are incompletely understood. Using a mouse model of NAFLD induced by a high-fat diet (obesity) and low-dose streptozotocin (type II diabetes), the present study explored a potential molecular signaling nexus linked to EXE-induced protection against obese diabetes-mediated NAFLD. METHODS: C57BL/6 female mice (8 weeks old) were randomly divided into three groups: normal diet (CON, n = 11), high-fat diet + streptozotocin (HFD + STZ, n = 11) and high-fat diet + streptozotocin + endurance exercise (HFD + STZ + EXE, n = 11). The mice assigned to the HFD + STZ + EXE group performed treadmill running exercise for 60 min/day, five days/week for 15 weeks, with HFD/HF diet continued throughout the experimental period. RESULTS: 15 weeks of EXE significantly attenuated obese diabetes-induced hepatic steatosis (e.g., reduced lipid droplet size) as a result of improved hepatic fatty acid oxidation evidenced by upregulated proteins involved in transportation of plasma free fatty acids to cytoplasm (FABP-1) and to mitochondria (CPT1A and CPT2b), and fatty acid activation (ACSL1). Our study also showed that EXE attenuated NAFLD-induced endoplasmic reticulum (ER) stress evidenced by repressed levels of ER stress markers (p-PERK, p-eIFa, p-IRE, Calpain 2, and cleaved alpha II spectrin). Furthermore, while NAFLD interfered in autophagy flux, EXE ameliorated the autophagy dysfunction. Intriguingly, despite NAFLD-induced hepatic steatosis, metabolic distress, ER stress, and aberrant autophagy, indicators of apoptotic cell death (CASPASE 12 and cleaved CASPASE 3) did not differ among groups. This observation suggests that hepatic steatosis may not cause cellular deterioration but that a transition to exacerbating progression due to extended metabolic distress may be responsible for massive hepatocyte injuries. CONCLUSIONS: Our study indicates that EXE-induced metabolic reprograming (e.g., enhanced lipid oxidation) and prevention of ER stress and autophagy dysfunction may play a crucial role in preventing metabolic distress-induced hepatic steatosis.