Exerkines: Benign adaptation for exercise and benefits for non-alcoholic fatty liver disease

Exercise has multiple beneficial effects on human metabolic health and is regarded as a "polypill" for various diseases. At present, the lack of physical activity usually causes an epidemic of chronic metabolic syndromes, including obesity, cardiovascular diseases, and non-alcoholic fatty liver disease (NAFLD). Remarkably, NAFLD is emerging as a serious public health issue and is associated with the development of cirrhosis and hepatocellular carcinoma. Unfortunately, specific drug therapies for NAFLD and its more severe form, non-alcoholic steatohepatitis (NASH), are currently unavailable. Lifestyle modification is the foundation of treatment recommendations for NAFLD and NASH, especially for exercise. There are under-appreciated organs that crosstalk to the liver during exercise such as muscle-liver crosstalk. Previous studies have reported that certain exerkines, such as FGF21, GDF15, irisin, and adiponectin, are beneficial for liver metabolism and have the potential to be targeted for NAFLD treatment. In addition, some of exerkines can be modified for the new proteins and get enhanced functions, like IL-6/IC7Fc. Another importance of exercise is the physiological adaptation that combats metabolic diseases. Thus, this review aims to summarize the known exerkines and utilize a multi-omics mining tool to identify more exerkines for the future research. Overall, understanding the mechanisms by which exercise-induced exerkines exert their beneficial effects on metabolic health holds promise for the development of novel therapeutic strategies for NAFLD and related diseases.