Exercise as a Multisystem Therapy for Metabolic Disorders: Integrating Inter-Organ Communication and Caveolar Signaling

Metabolic disorders, including obesity, type 2 diabetes mellitus (T2DM), dyslipidemia, and metabolic dysfunction–associated fatty liver disease (MAFLD), represent a major and escalating global health burden. These conditions are now recognized as systemic disorders arising from dysregulated inter-organ communication among metabolically active tissues. Central mechanisms include insulin resistance, chronic low-grade inflammation, oxidative stress, mitochondrial dysfunction, and neuroendocrine dysregulation. Exercise is increasingly recognized as a potent multisystem therapeutic intervention. Beyond energy expenditure, it induces coordinated molecular adaptations across tissues, including improved mitochondrial function, reduced inflammation, and enhanced metabolic flexibility. Exercise-induced signaling molecules (exerkines) and gut microbiota remodeling further mediate systemic metabolic benefits. This review synthesizes current evidence on exercise as an integrative therapy for metabolic disorders, with emphasis on molecular mechanisms, organ-specific adaptations, and clinical applications. Emerging roles of membrane microdomains such as caveolae are discussed as potential regulators of metabolic signaling, although their role in exercise adaptation remains incompletely defined.