Exerkines in precision management of metabolic diseases

Regular physical activity exerts systemic metabolic benefits that are pivotal for preventing and managing metabolic diseases. These effects are mediated in part by exerkines, which are signaling molecules released from various organs in response to exercise. Exerkines encompass polypeptides, nucleic acids, and bioactive lipids that collectively orchestrate metabolic adaptations. Recent metagenomic analyses have identified the gut microbiota as an additional source of exercise-responsive factors that modulate host metabolism and may influence individual responsiveness to training. Together, these diverse exerkines coordinate interorgan communication, enhance insulin sensitivity, maintain glucose and lipid homeostasis, and modulate inflammatory pathways. This review summarizes representative exerkines from skeletal muscle, adipose tissue, and liver, including interleukin-6, myostatin, fibroblast growth factor 21, adiponectin, and growth differentiation factor 15, which have shown promising therapeutic efficacy in preclinical studies and clinical trials for complex metabolic diseases. We also discuss microbiota-derived metabolites such as short-chain fatty acids that improve glucose and lipid metabolism, as well as host-derived metabolites including N-lactoyl-phenylalanine, betaine, and β-aminoisobutyric acid that regulate appetite, substrate utilization, and insulin action. Furthermore, we highlight recent progress in understanding how dynamic regulation of these exerkines mediates the metabolic benefits of exercise and their potential as targets for precision management of metabolic diseases. Understanding these molecular mediators of exercise provides a framework for integrating physical activity with pharmacological and nutritional strategies to improve metabolic health.