Exercise-induced signaling molecules and their systemic effects on organ function This figure illustrates how physical activity triggers the release of exerkines - bioactive proteins and metabolites from skeletal muscle, liver, adipose tissue, and platelets that circulate throughout the body and coordinate multi-organ adaptations. These compounds link exercise to improved function in the brain, vasculature, metabolism, and immune system. 1️⃣ Skeletal muscle as an endocrine organ Contracting muscle fibers secrete myokines such as IL-6, irisin (FNDC5), apelin, and cathepsin B (CTSB), which act on distant tissues to regulate metabolism and inflammation. 🟢 Example: IL-6 released during endurance exercise enhances glucose uptake in skeletal muscle and promotes fat oxidation in the liver, improving insulin sensitivity. 🟢 Example: Irisin stimulates browning of white adipose tissue and increases brain BDNF expression, linking muscular activity to both metabolic and cognitive benefits. 2️⃣ Liver-derived hepatokines The liver responds to exercise through the secretion of FGF21, IGF-1, and Gpld1, mediating systemic energy balance and neurovascular health. 🟢 Example: FGF21 promotes fatty acid oxidation and ketogenesis, supporting endurance metabolism and neuroprotection under metabolic stress. 🟢 Example: IGF-1 enhances angiogenesis and neural growth, improving cerebral perfusion and synaptic repair. 3️⃣ Adipose tissue signaling Adipocytes release adipokines such as adiponectin and apelin that modulate vascular tone, energy metabolism, and inflammation. 🟢 Example: Adiponectin improves insulin sensitivity, lowers hepatic fat accumulation, and protects endothelial cells from oxidative injury. 🟢 Example: Exercise-induced apelin enhances cardiac contractility and glucose utilization, improving cardiometabolic efficiency. 4️⃣ Platelet-derived factors Exercise activates platelets to release neurotrophic and regenerative mediators including BDNF and PF4. 🟢 Example: Circulating BDNF crosses the blood–brain barrier and promotes neurogenesis, while PF4 supports hippocampal regeneration and cognitive performance. 5️⃣ Metabolic intermediates as signaling molecules Exercise elevates metabolites that serve both as energy substrates and signaling mediators. 🟢 Example: Lactate enhances angiogenesis and neurotrophic factor expression. 🟢 Example: β-hydroxybutyrate (BHB) and NAD⁺ improve mitochondrial function and redox balance across organs, supporting resilience against metabolic stress. 6️⃣ Integrated systemic outcomes Through exerkine signaling, exercise orchestrates a network of inter-organ communication that enhances cardiovascular performance, stabilizes metabolism, and promotes brain plasticity. 🟢 Example: Regular training raises circulating FGF21, IL-6, and adiponectin, producing coordinated improvements in liver lipid handling, vascular health, and cognitive endurance.