Exercise Training Induces a Hepatic Memory Associated with Improved Glucose Control and Hepatic Secretory Function

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a global healthcare challenge. While increasing physical activity through exercise is considered a powerful therapy against MAFLD, its long-term effects on liver function remain unclear. This study aimed to investigate how exercise elicits hepatic memory, hypothesizing that exercise training cycles enhance long-term liver function and metabolic health, which persist after exercise cessation and are amplified with retraining. Here, 8-week-old male mice were fed a control diet and assigned to endurance-(voluntary wheel running; VWR) or resistance-based training (progressive weighted wheel running; PoWeR), or were sedentary (SED) and monitored throughout successive training (4 weeks), detraining (4 weeks), and retraining cycles (4 weeks). In vivo glucose homeostasis and hepatic function were assessed at each time point. We proposed that resistance-based training would yield superior metabolic outcomes. Both endurance (VWR) and resistance training (PoWeR) groups maintained lower body weight throughout training cycles, compared to SED, and following retraining, both training modalities resulted in fat mass reductions and increased lean mass, with PoWeR showing superior effects. While VWR only improved glucose tolerance (GTT) after retraining, PoWeR training robustly enhanced glucose (GTT) and pyruvate tolerance (PTT, and indirect marker of hepatic function) following training and retraining. Next, we studied the hepatic transcriptional adaptations (RNA-seq) and identified an upregulation of genes associated with hepatic secretory functions (Herpes simplex) following retraining including ~70 zinc finger protein (Zfp). Moreover, we identified that endurance retraining induced a group of hepatic carboxylesterases ( Ces2b, Ces3b, Ces4a ), which play a key role in complex lipid clearance from circulation. Greater liver expression of carboxylesterases was associated with higher serum carboxylesterase enzymatic activity (assessed by substrate cleavage). Additionally, PoWeR mice showed higher hepatic Ces2b expression and CES activity, particularly after training, further supporting the role of exercise in enhancing hepatic secretary function. Our findings indicate that exercise induces a hepatic memory that is potentiated by retraining and may be associated with glucose regulation and lipid metabolism. Notably, resistance-based training persistently enhanced the hepatic glucoregulatory function. Our study highlights the powerful effect of exercise as a targeted intervention for improving long-term metabolic health in MAFLD. Funding was provided by the Campus Research Board at the University of Illinois Urbana-Champaign. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.