Exercise intensity modulates the human plasma secretome and interorgan communication

Exercise is recognized as first-line therapy for many cardiometabolic diseases, including obesity, type 2 diabetes, and hypertension. Despite the abundant health-promoting effects of exercise, in-depth characterization of circulatory factors that mediate these benefits in humans remains incomplete. Moreover, how different modes and intensities of exercise uniquely regulate these processes is unclear. Here, we address these questions by conducting a multi-cohort human exercise intervention, incorporating sprint-interval exercise (SIE) and moderate-intensity exercise (MIE) to analyze intensity-dependent regulation of interorgan crosstalk. We find that exercise intensity distinctly influences the plasma proteome and metabolome in both untrained and trained participants. SIE led to immediate and robust changes to the plasma proteome, whereas MIE resulted in delayed secretory kinetics. By leveraging large, multi-organ gene and protein expression datasets, in combination with <i>in vitro</i> and <i>in vivo</i> tissue sampling, we map the differentially regulated proteins to their predicted tissue of origin and destination. We find that adipocytes are particularly sensitive to exercise intensity, undergoing broad transcriptomic remodeling following <i>in vitro</i> incubation with SIE as compared to MIE plasma. These findings underscore the integrated whole-body response following acute exercise and highlight exercise intensity as a key factor influencing interorgan communication.