Combined Cold Exposure and Exercise Improves NAFLD: Mechanistic Insights.

Abstract

Introduction: Non-alcoholic fatty liver disease (NAFLD) affects a quarter of the global population and poses a remarkably serious threat to human health.

Objectives: The effect and potential molecular mechanisms of combined cold exposure and exercise intervention on NAFLD remain unclear.

Materials and methods: A high-fat diet-induced NAFLD mouse model was utilized. Twenty-four NAFLD mice were divided into three groups and subjected to cold exposure (5 °C), regular-temperature exercise (22 °C), or combined cold exposure and exercise (5 °C) for 8 weeks, 5 days a week, once daily for 1 hour each session. Intervention effects were evaluated through bodyweight, liver mass, liver/bodyweight ratio, blood lipid profile, circulating fibroblast growth factor 21 (FGF21) levels, and liver histopathology. Immunoblotting and quantitative PCR were employed to assess the protein and gene expression of liver FGF21, β-klotho, and FGFR1 to preliminarily elucidate the molecular mechanisms underlying NAFLD improvement by combined cold exposure and exercise.

Results: Compared with cold exposure or regular-temperature exercise alone, combined cold exposure and exercise significantly reduced the bodyweight, liver weight, and liver/ bodyweight ratio in the NAFLD mice. The levels of blood lipids, circulating FGF21, and liver glycogen also significantly decreased. Furthermore, the combined intervention significantly reduced liver fat deposition and fibrosis and significantly increased the expression of FGFR1 and β-klotho proteins, suggesting the activation of the FGF21-β-klotho/FGFR1 signaling pathway.

Conclusions: This preclinical study demonstrates that combined cold exposure and exercise synergistically alleviates NAFLD progression in animal models, primarily by activating the FGF21-β-klotho/FGFR1 pathway to enhance lipid metabolism and reduce liver injury. These findings highlight the translational potential of dual environmental and behavioral interventions, providing a mechanistic foundation for developing non-pharmacological therapies targeting metabolic pathways in humans, particularly for NAFLD patients resistant to conventional lifestyle modifications or pharmacotherapy.