Lijun Zhou, Huanyu Long, Hamid Alizadeh
The global prevalence of obesity and metabolic disorders presents a substantial public health issue, with projections indicating that, by 2035, approximately 54% of the worldwide adult population will be classified as having overweight or obesity. Exercise immunometabolism has developed as a field investigating the mechanistic interplay between physical activity and the reciprocal regulation of immune and metabolic processes. Central to this paradigm are myokines, cytokines secreted by skeletal muscle during contraction, mediating the systemic benefits of exercise. Myokine meteorin-like protein (Metrnl) has attracted scientific attention due to its multiple roles in health and disease, including both protective metabolic effects and potential involvement in cancer progression. This review synthesizes current knowledge on Metrnl as an exercise-responsive myokine, examining its molecular regulation and its modulation by various exercise modalities, with high-intensity and resistance training showing the most pronounced effects. We present evidence from both preclinical models and clinical studies of Metrnl's anti-inflammatory and metabolic actions across multiple organ systems, including its role in mediating muscle-adipose, muscle-pancreas, muscle-cardiovascular, muscle-liver, muscle-immune, and muscle-brain crosstalk. Preclinical research has demonstrated Metrnl's effects on glucose homeostasis, insulin sensitivity, adipose tissue browning, and cardiovascular function while attenuating inflammation, with clinical studies beginning to validate these findings in humans. Despite promising results, challenges remain in translating these insights into clinical practice, including variability in human responses and knowledge gaps regarding demographic influences. This review addresses these translational challenges and proposes future research directions to utilize the therapeutic potential of Metrnl in metabolic and inflammatory disorders.