Can Myokines Serve as Supporters of Muscle–Brain Connectivity in Obesity and Type 2 Diabetes? Potential of Exercise and Nutrition Interventions

Background/Objectives: Skeletal muscle–derived myokines have emerged as pivotal mediators of the muscle–brain axis, linking peripheral metabolic regulation with central nervous system function. These molecules may influence skeletal muscle maintenance, neuroplasticity, neuroinflammation, and cognitive performance, and their dysregulation is increasingly associated with metabolic and cognitive impairment. In obesity (OB) and type 2 diabetes mellitus (T2DM), dysregulated myokine profiles characterized by reduced levels of irisin, brain-derived neurotrophic factor (BDNF), and cathepsin B (CTSB) have been reported and may contribute to the development of both sarcopenia and cognitive impairment. This review aims to summarize current evidence on myokine alterations in OB and T2DM and to evaluate how exercise- and nutrition-based interventions may modulate the muscle–brain axis to support metabolic and cognitive health. Methods: This narrative review synthesizes experimental, clinical, and translational studies examining (1) alterations in circulating myokines in OB and T2DM, (2) associations between myokines, skeletal muscle function, and neurocognitive outcomes, and (3) the modulatory effects of exercise and specific nutrients on myokine-mediated muscle–brain communication. Results: Available evidence indicates that OB and T2DM are frequently accompanied by reduced circulating levels of beneficial myokines such as irisin, BDNF, and CTSB, which may impair skeletal muscle integrity and contribute to cognitive decline. Restoring favorable myokine signaling through physical activity appears to enhance skeletal muscle maintenance, neuroplasticity, and metabolic homeostasis. Emerging data further suggest that selected nutrients can mimic or potentiate some exercise-induced myokine responses, thereby supporting both muscle and brain function. Collectively, these findings imply that combined exercise and nutrition strategies may exert synergistic or additive effects by reinforcing inter-organ communication along the muscle–brain axis. Conclusions: This review outlines current evidence on myokine alterations observed in OB and T2DM and discusses how exercise- and nutrition-based approaches may modulate the muscle–brain axis to mitigate metabolic dysfunction and preserve cognitive health. Targeting beneficial myokine pathways through tailored lifestyle interventions represents a promising avenue to support both skeletal muscle and neurocognitive function in individuals with metabolic disease.