Understanding why two people following identical exercise programs achieve vastly different metabolic outcomes has long frustrated clinicians and researchers alike. The emerging science of exerkines — signaling molecules released by muscle, fat, liver, and even gut bacteria in response to physical activity — may finally offer a mechanistic explanation, and potentially a therapeutic roadmap for conditions like type 2 diabetes, obesity, and metabolic syndrome.
This comprehensive review synthesizes current knowledge on how exercise triggers the release of biochemically diverse molecules that coordinate systemic metabolic adaptation. Among the most studied are skeletal muscle–derived interleukin-6 and myostatin, liver-secreted fibroblast growth factor 21 (FGF21), adipose-released adiponectin, and growth differentiation factor 15 (GDF15) — each demonstrating measurable effects on insulin sensitivity, lipid clearance, and inflammatory tone in both preclinical models and human trials. The review also spotlights microbiota-derived metabolites, particularly short-chain fatty acids produced during exercise-responsive shifts in gut ecology, alongside host-generated small molecules including N-lactoyl-phenylalanine, betaine, and β-aminoisobutyric acid, which regulate appetite signaling and substrate utilization.
What elevates this review beyond a catalog of molecules is its framing around inter-organ communication — the idea that exercise does not simply condition muscle but orchestrates a multi-tissue dialogue. This perspective aligns with a growing body of research suggesting the gut microbiome is not a passive bystander but an active participant in training adaptation, which could explain individual variability in exercise response. The practical implication is significant: rather than prescribing uniform exercise protocols, future clinical strategies might profile a patient's exerkine signature to personalize intensity, modality, and even adjunct nutritional interventions. Most findings remain preclinical or from small human studies, so translational caution is warranted. Still, exerkines represent one of the more credible frameworks connecting physical activity to precision medicine, making this review a valuable consolidation of a rapidly maturing field.