Obesity is characterized by chronic low-grade inflammation, insulin resistance, impaired skeletal muscle function, and disturbances in neurovascular health. Metabolic inflexibility, defined as a reduced capacity to appropriately switch between lipid and glucose utilization in response to physiological demands, represents a central pathophysiological feature linking these alterations. Emerging evidence suggests that physical exercise and vitamin D status influence overlapping molecular pathways involved in energy metabolism, inflammation, vascular function, and neural signaling. Exercise robustly improves mitochondrial function, endothelial health, and myokine-mediated cross-talk between muscle, adipose tissue, and the brain, while vitamin D, acting through the vitamin D receptor (VDR), modulates calcium homeostasis, immune signaling, and tissue-specific metabolic responsiveness. This narrative review synthesizes mechanistic and translational evidence on how vitamin D and exercise may interact within a neurovascular–muscle axis to influence metabolic regulation, adipose inflammation, skeletal muscle adaptation, and neurocognitive function in obesity. Importantly, current evidence supports exercise as the primary driver of metabolic improvement, whereas vitamin D may exert context-dependent, adjunctive effects, particularly in deficient populations. Rather than proposing a standalone therapy, this review situates the vitamin D–exercise interaction as a complementary strategy that may enhance functional and systemic adaptations relevant to obesity-related complications. Limitations related to causal inference and population heterogeneity are highlighted, underscoring the need for well-powered, obesity-specific clinical trials to clarify translational relevance.
Zheng et al. (Thu,) studied this question.