Adipose Tissue Dysfunction and Metabolic Diseases: The Role of Vitamin D/Vitamin D Receptor Axis

Abstract

Obesity-associated adipose tissue dysfunction represents a key driver of metabolic disorders, including type 2 diabetes, cardiovascular diseases, and fatty liver disease. Emerging evidence highlights the vitamin D/vitamin D receptor (VD/VDR) axis as an important regulator of adipose tissue homeostasis. Beyond its classical role in mineral metabolism, vitamin D influences adipogenesis, inflammation, and insulin sensitivity, thereby modulating systemic metabolic health. In this review, we summarize the current understanding of the VD/VDR axis in adipose tissue biology, from molecular pathways controlling lipid turnover and immune responses to experimental and clinical evidence linking vitamin D status with obesity-related complications. We also discuss the role of genetic variability and tissue-specific VDR signaling in shaping metabolic outcomes. While results from supplementation trials remain inconsistent, maintaining adequate vitamin D levels appears crucial for the prevention of adipose tissue dysfunction and its cardiometabolic consequences. Future studies are warranted to define optimal strategies for harnessing the VD/VDR axis in therapeutic approaches to obesity and metabolic disease.

Keywords: adipokines; adipose tissue dysfunction; inflammation; insulin resistance; obesity; vitamin D (VD); vitamin D receptor (VDR).

Figure 1

Vitamin D metabolism and VDR-mediated regulation in adipose tissue. Vitamin D₃, synthesized in the skin upon UVB exposure, is hydroxylated in the liver to 25(OH)D and in the kidney to the active form 1,25(OH)₂D (calcitriol). This metabolite binds to the vitamin D receptor (VDR), a nuclear receptor expressed in adipose tissue, where it modulates gene transcription [28]. VDR activation influences adipocyte differentiation, insulin sensitivity, and the inflammatory profile of adipose tissue by downregulating pro-inflammatory cytokines (TNFα, IL-6, and MCP-1) and upregulating adiponectin, thereby contributing to metabolic homeostasis [29]. Legend: Arrows: ↑ increase; ↓ decrease.

Figure 2

VD/VDR axis in rodent adipose tissue. In rodents, HF-diet effects on total 25(OH)D are inconsistent—driven by diet composition and assay—whereas free 25(OH)D consistently falls; 1,25(OH)₂D responses vary. VDR^−/− mice show ↑ energy expenditure and FA oxidation with caveats (rescue diet, systemic deletion, alopecia). Adipocyte VDR overexpression increases fat mass/weight and lowers energy expenditure/FA oxidation; adipose VDR deletions yield promoter-/sex-/context-dependent results. Legend: Blue = VDR^−/−; Red = adipocyte human VDR overexpression; Green = high-fat diet (assay & diet dependent). Arrows: ↑ increase; ↓ decrease. Abbreviations: VD, vitamin D; VDR, vitamin D receptor; FA, fatty acid.