Adiponectin mediates the additive effects of combining daily exercise with caloric restriction for treatment of non-alcoholic fatty liver

Background/Objectives: Little is known regarding whether or not combining daily exercise (EX) with caloric restriction (CR) additionally alleviates non-alcoholic fatty liver disease (NAFLD). The study investigated the effect of the combination of EX and CR on NAFLD and its underlying mechanisms in high-fat diet (HFD)-induced obese mice.Methods: C57BL/6 mice (N=50) were fed a standard chow (SC; n=10) or HFD (n=40) for 24 weeks. After 16 weeks, the HFD mice were further assigned to one of the following groups for the remaining 8 weeks: the first group of mice (HFD; n=10) remained to HFD, the second group of mice (HFD-EX; n=10) remained to HFD while subjected to EX, the third group of mice (HFD-CR; n=10) switched their diet from HFD to SC and the fourth group of mice (HFD-EX+CR; n=10) switched their diet from HFD to SC while simultaneously being subjected to EX. Results: HFD resulted in obesity, impaired glucose tolerance, hypercholesterolemia and histology-based hepatic steatosis in conjunction with hypoadiponectinemia and downregulation of hepatic adiponectin receptors. However, EX or CR alleviated the fatty liver and its metabolic complications significantly. Compared with EX or CR alone, the combination of EX and CR resulted in further alleviations of NAFLD-associated conditions. The additive benefits of the combined treatment were associated with greater elevations of adiponectin and its hepatic receptors, in conjunction with greater expression of their downstream targets involved in fatty acid oxidation, de novo lipogenesis and anti-inflammation. Conclusions: The current findings provide experimental evidence in favor of the combination of EX and CR as a superior strategy for NAFLD treatment than EX or CR alone.