Exercise and cold exposure as dual physiological stressors in MASLD: AMPK-mediated metabolic adaptation and interorgan crosstalk

Shijie Wang, Yuan Gao, Yue Wang, Yi-Xiang Wang, Ying Liu

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become one of the most prevalent chronic liver diseases worldwide. Its disease spectrum can progress from simple hepatic steatosis to metabolic dysfunction-associated steatohepatitis (MASH), liver fibrosis, cirrhosis, and even hepatocellular carcinoma. Despite recent advancements in targeted pharmacological therapies for MASH, limitations persist regarding applicable populations and long-term benefits. Therefore, various lifestyle interventions, including dietary management and regular exercise, remain the cornerstone of MASLD management. AMP-activated protein kinase (AMPK), as an energy sensor, coordinates lipid synthesis, fatty acid oxidation, mitochondrial homeostasis, autophagy, and inflammatory responses under conditions of energy stress, thereby representing a key molecular hub connecting exercise, cold exposure, and the ameliorative effects on MASLD. Based on a narrative synthesis of mechanistic and translational evidence, this article summarizes the effects of exercise intervention, cold exposure, and their combination on AMPK-related pathways and further elucidates the potential mechanisms in terms of hepatic lipid metabolism, brown/beige adipose thermogenesis, skeletal muscle-adipose tissue-liver interorgan crosstalk, and mitochondrial quality control. Current evidence, particularly from animal and mechanistic studies, suggests that exercise and cold exposure may regulate MASLD-related metabolic abnormalities through the AMPK/ACC/SREBP1c, AMPK/SIRT1/PGC-1α and AMPK/mTOR/TFEB pathways, as well as AMPK-related myokine/hepatokine networks. The combined intervention remains an emerging strategy; preclinical data indicate potential additive effects on energy expenditure and lipid clearance, but synergistic mechanisms, optimal temperature conditions, clinical safety, and long-term efficacy require further validation.