Creatine and essential amino acids with exercise in obesity: an immunometabolic perspective on the muscle-adipose-brain axis.

Obesity is associated with anabolic resistance, skeletal muscle dysfunction, adipose tissue dysregulation, chronic low-grade inflammation, and altered brain metabolism. Exercise is a primary strategy for counteracting these disturbances, while nutritional interventions may complement exercise-induced adaptations. Creatine and essential amino acids (EAAs) have established roles in muscle bioenergetics and protein synthesis, respectively, but their combined use with exercise and potential effects on the interconnected muscle-adipose-brain axis in obesity remain incompletely characterized. This review examines mechanistic and clinical evidence for creatine and EAA supplementation alongside exercise, with emphasis on muscle anabolism, body composition, adipose remodeling, immunometabolism, and muscle-adipose-brain communication. Exercise provides the principal physiological stimulus for muscle adaptation, whereas EAAs, particularly leucine, stimulate muscle protein synthesis through amino acid-sensing and mTORC1-related pathways. Creatine increases phosphocreatine availability and may enhance training capacity, strength, and lean mass when combined with resistance exercise. Available evidence suggests potentially complementary, rather than established synergistic, effects of creatine and EAAs with exercise on muscle preservation, functional capacity, and body composition. Beyond muscle, exercise-derived myokines, exerkines, adipokines, and metabolites provide plausible mechanisms linking peripheral adaptations to adipose tissue and the brain. Creatine may support cellular and cerebral bioenergetics, whereas EAAs influence amino acid availability and protein turnover. However, direct evidence that these interventions modify obesity-associated neuroinflammation, depression, or cognitive dysfunction remains limited. Overall, current evidence supports exercise as the central intervention, with creatine and EAAs representing potentially complementary nutritional strategies. Evidence for integrated effects on adipose-brain communication, immunometabolism, and neurobehavioral outcomes remains preliminary and is derived substantially from indirect or preclinical findings. Future randomized trials should directly compare individual and combined interventions, establish optimal dosing and timing, and integrate mechanistic biomarkers with clinically relevant metabolic and neurobehavioral outcomes.