Exercise as a multisystem signaling therapy: A hypothesis integrating inter-organ communication and membrane microdomain regulation in metabolic disease.

Exercise is a powerful non-pharmacological intervention for metabolic diseases, yet current mechanistic explanations remain fragmented across individual organs. This review proposes that exercise may act as a multisystem signaling therapy, generating interdependent mechanical, endocrine, metabolic, inflammatory, and redox cues that integrate communication among skeletal muscle, adipose tissue, liver, endothelium, and the central nervous system. We introduce a conceptual model in which caveolae, cholesterol-rich membrane microdomains formed by caveolins and cavins, serve as a spatial platform that helps cells interpret and integrate these diverse extracellular signals into unified intracellular responses. Evidence already supports caveolar roles in mechanotransduction, insulin receptor organization, lipid handling, nitric oxide signaling, and membrane tension buffering. However, direct causal links between exercise-induced caveolar remodeling and whole-body metabolic adaptation remain limited. Rather than positioning caveolae as the sole regulator of exercise responses, this review synthesizes current findings across tissues, differentiates established mechanisms from emerging hypotheses, and evaluates how exercise modality, tissue context, and metabolic disease states may shape caveolae-dependent signaling. We outline experimental strategies capable of testing this framework and highlight key gaps that must be addressed before caveolae-targeted interventions can be translated clinically. By integrating systems physiology with membrane biology, this review provides a mechanistically grounded and testable model for understanding how exercise coordinates metabolic homeostasis through spatial regulation of cellular signaling.