The skeletal muscle-adipose creatine metabolic axis: A novel paradigm for lipid metabolism reprogramming and obesity management.

The global prevalence of obesity and related metabolic disorders has spurred interdisciplinary research to develop new intervention strategies. Current research is increasingly focusing on the exercise-induced browning of white adipose tissue and the mechanisms by which it improves energy metabolism. Creatine, as the primary carrier of high-energy phosphate bonds within cells, is gaining attention for its role in the metabolic reprogramming of adipose tissue. This review aims to clarify the synergistic regulatory mechanisms between exercise and creatine metabolism, and introduces an innovative 'skeletal muscle-adipose creatine metabolic axis' model. Exercise may upregulate the expression of the creatine transporter in skeletal muscle by activating the AMP-activated protein kinase/peroxisome proliferator-activated receptor γ coactivator 1-α signalling pathway, enhancing phosphocreatine shuttle kinetics, and thereby increasing energy metabolism efficiency. Concurrently, exercise-induced exosomes or miRNAs from skeletal muscle may regulate the futile creatine cycle in adipose tissue and activate non-uncoupling protein 1-dependent thermogenic pathways, thus alleviating obesity conditions. This model not only reveals the multi-organ cross-talk mechanism mediated by exercise in lipid metabolism regulation but also provides a theoretical basis for creatine metabolism-targeted obesity interventions.