Exercise Rewires the Body's Hormonal Communication Network Across Multiple Organs

Exercise is widely recognized as one of the most powerful interventions for cardiometabolic, neurological, and immune health, yet the full scope of how it rewires communication between organs remains poorly understood. This study addresses that gap by applying a systems genetics framework to the most comprehensive preclinical exercise dataset available—the MoTrPAC rat endurance training study—to quantify how 8 weeks of treadmill running remodels inter-organ endocrine networks.

The researchers employed two complementary computational tools. QENIE (Quantitative Endocrine Network Interaction Estimation) assigns a 'secretome score' to each known secreted protein in an origin tissue based on how strongly its expression correlates with gene expression patterns across a target tissue, providing a quantitative estimate of endocrine impact. GD-CAT (Gene-Derived Correlations Across Tissues) then identifies which biological pathways in the target tissue are associated with that endocrine signal. Together, these tools were applied to transcriptomic and proteomic data from 16 tissues in male and female rats across training durations of 1, 2, 4, and 8 weeks, generating over 1,500 unique secretome score datasets.

The framework was first validated against established exercise biology. Leptin's secretome score from subcutaneous white adipose tissue (scWAT) to the hypothalamus increased progressively with training, and GD-CAT revealed that trained rats uniquely showed upregulation of neuronal synapse and neurotransmitter receptor pathways—consistent with known training-enhanced hypothalamic leptin sensitivity. Similarly, the myokine IL-15's score from gastrocnemius to scWAT was over four-fold higher in 8-week trained rats, with correlated upregulation of lipid catabolism in adipose tissue matching IL-15's known lipolytic role. TGF-β2's autocrine score in scWAT also increased with training, linked to mitochondrial metabolism upregulation and reduced inflammation.

At a systems level, scWAT emerged as the dominant endocrine origin tissue after 4–8 weeks of training, surpassing vena cava which led in early training weeks. The scWAT-to-vastus lateralis connection showed the highest significance and effect size of any tissue pair, underscoring adipose-to-skeletal muscle crosstalk as a primary axis remodeled by endurance training. Globally, extracellular matrix (ECM)-derived secretory factors and Wnt signaling ligands were identified as broadly regulated across multiple tissues, suggesting these pathways serve as core mediators of exercise-induced inter-organ communication. At the protein level, lung-to-cerebral cortex and gastrocnemius-to-heart connections were among the most differentially regulated pairs.

This work provides an unprecedented atlas of exercise-remodeled endocrine networks and a computational resource for novel exerkine discovery. The identification of Wnt signaling and ECM factors as globally regulated secretory features opens new avenues for understanding how exercise produces systemic benefits, including potential implications for aging, metabolic disease, and tissue regeneration.