Endurance exercise elicits a hepatic memory associated with improved metabolic function and protein secretion

Area of Science:

• Exercise physiology
• Metabolic health
• Liver disease

Background:

• Endurance exercise offers protection against metabolic dysfunction-associated steatotic liver disease (MASLD).
• The persistence of these protective effects after training cessation is not well understood.
• Investigating the concept of a 'hepatic memory' of exercise is crucial for understanding long-term metabolic benefits.

Purpose of the Study:

• To determine if the metabolic benefits of endurance exercise persist after training cessation.
• To investigate the underlying mechanisms of this 'hepatic memory' in mice and humans.
• To explore the role of specific liver pathways and enzymes in maintaining exercise-induced metabolic improvements.

Main Methods:

• Utilized endurance training cycles in mice to isolate hepatic memory.
• Conducted liver transcriptomic analysis to identify affected pathways.
• Measured serum lipid profiles, enzyme activities, and protein levels.
• Examined the effects under an obesogenic diet challenge and in human participants.

Main Results:

• Endurance retraining persistently reduced hepatic steatosis and improved glucoregulation.
• Retraining upregulated hepatic carboxylesterases (CES) and increased circulating carboxylesterase activity.
• Enhanced delivery of phosphatidylcholines (PC) and lysophosphatidylcholines (lysoPC) to working muscle was observed.
• The hepatic memory of exercise demonstrated resilience under an obesogenic diet and was observed in humans with prior training.

Conclusions:

• Endurance retraining establishes a persistent hepatic exercise memory.
• This memory involves transcriptional reprogramming and lipid remodeling, conferring resilience against MASLD.
• The PPAR-RXR-clock axis may be involved in coordinating lipid delivery and fatty acid oxidation.