Exerkine-Mediated Inter-Organ Crosstalk and Translational Perspectives in Metabolic Diseases

Exercise is a cornerstone intervention for obesity and related metabolic diseases. However, its systemic benefits cannot be fully explained by increased energy expenditure, enhanced skeletal muscle glucose uptake, reduced adiposity, or improved peripheral insulin sensitivity alone. We review recent advances in exercise-responsive exerkines, with a focus on how these factors coordinate inter-organ crosstalk among major metabolic organs, including skeletal muscle, adipose tissue, liver, pancreas, and intestine.

Both acute exercise and chronic training change the secretory profiles of multiple organs, giving rise to a broad spectrum of exercise-responsive factors, including proteins, metabolites, lipids, nucleic acids, and extracellular vesicle-associated cargo. Collectively, these exerkines coordinate inter-organ communication and regulate systemic energy homeostasis, inflammation, and tissue function, thereby promoting metabolic adaptation and mitigating lipotoxicity and insulin resistance. Among the candidates identified to date, IL-6, FGF21, GDF15, and myostatin have undergone relatively advanced translational investigation. Their development highlights both the therapeutic promise and the limitations of exerkine-based strategies, as illustrated by FGF21 analogues for metabolic diseases and the limited efficacy or tolerability reported for some GDF15-targeted interventions. Exerkines provide a molecular framework for understanding how exercise produces coordinated metabolic adaptations across organs. However, most candidate exerkines still require stronger human validation, clearer tissue-source attribution, defined receptor pathways, dose-response characterization, and long-term safety assessment. Exerkine-based strategies should therefore be viewed not as replacements for exercise, but as potential complementary approaches for populations with limited exercise capacity, including frail older adults, patients with cardiopulmonary disease, individuals with severe obesity or neuromuscular disorders, and those recovering from surgery or prolonged bed rest.