Beyond Vitamin D Deficiency: Maternal Diet, Metabolic Dysfunction, and Vitamin D Signaling in Developmental...

Within the Developmental Origins of Health and Disease (DOHaD) framework, maternal nutrition is an important component of the developmental environment that can shape long-term offspring metabolic and immune health. Western dietary patterns (WD), characterized by high energy density and greater consumption of saturated fats, refined carbohydrates, added sugars, and ultra-processed foods, are associated with metabolic and inflammatory disturbances that may influence fetal development. Experimental models further demonstrate that maternal high-fat and WD exposures can produce persistent metabolic alterations in offspring, supporting a role for maternal dietary composition in developmental programming. Vitamin D (VD) represents a potentially important regulatory system within this environment because VD signaling contributes to immune regulation, cellular differentiation, and metabolic homeostasis through vitamin D receptor (VDR)-mediated transcription. Although circulating 25-hydroxyvitamin D [25(OH)D] is the primary clinical indicator of VD status, effective VD activity also depends on tissue distribution, enzymatic metabolism, and VDR-mediated responsiveness. This review examines evidence linking maternal Western and high-fat dietary exposures with disruption of VD regulation during development, with particular emphasis on potential tissue-specific effects in offspring. Evidence across obesity and high-fat diet models, including maternal exposure models, suggests that metabolic dysfunction may influence several aspects of VD regulation, while maternal VD status has independently been associated with metabolic and developmental outcomes in offspring. However, evidence directly linking maternal WD exposure with altered VD regulation in individual offspring tissues remains limited. Consequently, it remains unclear whether maternal WD exposure produces persistent, tissue-specific alterations in offspring VD regulation and whether these changes occur alongside inflammatory dysregulation. Addressing this gap is particularly important because tissues differ in their expression of VDR and VD-metabolizing enzymes and may therefore respond differently to maternal metabolic stress.