Exercise Training Induces a Hepatic Memory that Synchronizes the Lipid Delivery to Skeletal Muscle

Endurance exercise is a powerful non-pharmacological strategy to improve metabolic health, but how these benefits persist after training stops remains poorly defined. Emerging studies point to the establishment of a muscle memory of exercise that can enhance muscle growth. The liver is central coordinator of whole-body metabolism, and adaptative responses in exercised muscle depend on effective hepatic metabolic support. Nevertheless, whether an analogous memory exists in the liver has not yet been determined. Here, we tested how endurance training induces a persistent hepatic metabolic memory capable of protecting against the metabolic consequences of an obesogenic diet. Eight-week-old male mice were fed either a control diet (CD; 10% kcal from fat) or a high-fat diet (HFD; 45% kcal from fat) and assigned to sedentary (SED, static cages) or endurance training (voluntary wheel running; VWR). Mice underwent 4-week training (4wk), 4-week detraining (8wk), and 4-week retraining periods (12wk). Timed-exercise CD-fed controls were used to isolate the effects of prior training. Metabolic health, tissue morphology, and transcriptomics were assessed at each time point. In HFD-fed mice, endurance retraining robustly reduced adiposity, significantly improved HOMA-IR, enhanced hepatic gluconeogenic regulation, and suppressed hepatic lipid accumulation. Hepatic transcriptomic analysis revealed that endurance retraining strongly activated hepatic protein and lipid secretory pathways independently from diet. Transcription factor prediction and comparative analysis between endurance retrained and exercise-naïve controls identified the PPARα/RXR–BMAL1/CLOCK/NPAS2 axis as a main pathway associated with the memory. Among the hepatic memory targets, retraining prominently induced carboxylesterase (Ces) gene expression and release, assessed by plasma CES activity, and improved plasma lipid profiles by raising HDL-C and lowering total triglycerides and LDL-C. Using Ldlr-knockout mice, we show that CES proteins directly associate with circulating lipoproteins primarily LDL particles and is inversely correlated with LDL-C levels. Moreover, retraining markedly increased hepatic, plasma, and muscle phosphatidylcholine (PC/LPC) species, which are known circadian lipids that stimulate skeletal muscle fatty acid oxidation. This hepatic PPARα–circadian secretory axis might provide a link for the coordinated response required for the exercise memory that enhances systemic lipid and glucose homeostasis. Our findings point to endurance exercise as an important factor that imprints a hepatic metabolic memory, reactivated upon retraining to protect against diet-induced metabolic dysfunction. This abstract was presented at the American Physiology Summit 2026 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.