Vitamin D and Metabolic Syndrome: Molecular Mechanisms and Clinical Implications: A Narrative Review

Metabolic syndrome (MetS) is a complex multisystem disorder characterized by insulin resistance, central obesity, dyslipidemia, hypertension, and chronic low-grade inflammation, all of which substantially increase the risk of type 2 diabetes mellitus and cardiovascular disease. The aim of this narrative review is to examine the role of vitamin D in the pathophysiology of MetS from a multisystem perspective. Specifically, it synthesizes current evidence on the molecular mechanisms through which vitamin D may influence inter-organ communication, insulin resistance, adipose tissue dysfunction, hepatic metabolism, skeletal muscle function, chronic inflammation, oxidative stress, and mitochondrial homeostasis, highlighting its potential contribution to the prevention and management of MetS. Current evidence indicates that MetS should not be regarded merely as a cluster of isolated metabolic abnormalities but rather as a disorder characterized by disrupted molecular signaling and impaired communication among metabolically active organs. In this context, experimental and preclinical evidence suggests that vitamin D, through activation of the vitamin D receptor (VDR), modulates key signaling pathways, including AMP-activated protein kinase (AMPK), the mechanistic target of rapamycin (mTOR), nuclear factor kappa B (NF-κB), and peroxisome proliferator-activated receptor gamma (PPAR-γ), thereby influencing insulin sensitivity, inflammation, oxidative stress, mitochondrial function, and metabolic homeostasis. Nevertheless, clinical evidence remains heterogeneous due, in part, to the lack of consensus regarding serum 25-hydroxyvitamin D thresholds for defining vitamin D status, as well as differences in baseline vitamin D concentrations, supplementation regimens, study populations, and methodological designs. Overall, the available evidence suggests that vitamin D should be considered an adjunct to lifestyle-based interventions rather than a stand-alone therapeutic strategy. Future research is warranted to clarify its clinical utility in the prevention and management of MetS.