Vitamin D and adipose tissue-more than storage

Abstract

The pandemic increase in obesity is inversely associated with vitamin D levels. While a higher BMI was causally related to lower 25-hydroxyvitamin D (25(OH)D), no evidence was obtained for a BMI lowering effect by higher 25(OH)D. Some of the physiological functions of 1,25(OH)2D3 (1,25-dihydroxycholecalciferol or calcitriol) via its receptor within the adipose tissue have been investigated such as its effect on energy balance, adipogenesis, adipokine, and cytokine secretion. Adipose tissue inflammation has been recognized as the key component of metabolic disorders, e.g., in the metabolic syndrome. The adipose organ secretes more than 260 different proteins/peptides. However, the molecular basis of the interactions of 1,25(OH)2D3, vitamin D binding proteins (VDBPs) and nuclear vitamin D receptor (VDR) after sequestration in adipose tissue and their regulations are still unclear. 1,25(OH)2D3 and its inactive metabolites are known to inhibit the formation of adipocytes in mouse 3T3-L1 cell line. In humans, 1,25(OH)2D3 promotes preadipocyte differentiation under cell culture conditions. Further evidence of its important functions is given by VDR knock out (VDR(-/-)) and CYP27B1 knock out (CYP27B1 (-/-)) mouse models: Both VDR(-/-) and CYP27B1(-/-) models are highly resistant to the diet induced weight gain, while the specific overexpression of human VDR in adipose tissue leads to increased adipose tissue mass. The analysis of microarray datasets from human adipocytes treated with macrophage-secreted products up-regulated VDR and CYP27B1 genes indicating the capacity of adipocytes to even produce active 1,25(OH)2D3. Experimental studies demonstrate that 1,25(OH)2D3 has an active role in adipose tissue by modulating inflammation, adipogenesis and adipocyte secretion. Yet, further in vivo studies are needed to address the effects and the effective dosages of vitamin D in human adipose tissue and its relevance in the associated diseases.

Keywords: 1,25-dihydroxycholecalciferol or calcitriol; adipogenesis; adipokines; adipose tissue; gene regulation; secretion; vitamin D binding protein.

Figure 1

Effect of 1,25(OH)₂D₃ on adipose tissue/lean and obese state. ^*Vitamin D levels (25(OH)D) according to the Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press, 2011.

Figure 2

Overview of 1,25(OH)₂D₃ on regulating factors in adipogenesis. 1,25(OH)₂D₃ has both stimulating and inhibition effect on adipogenesis. 1,25(OH)₂D₃ suppress dickkopf1(DKK1) and secreted frizzled-related protein 2 (SFRP2) expression in mouse bone marrow stromal cells (BMSCs) there by suppressing adipogenic peroxisome proliferator-activated receptor γ/retinoid X receptor complex (PPARγ/RXRα) mediated by stabilization of β-catenin through wingless-type MMTV integration site family, member 10 (WNT10) inhibition. Furthermore, 1,25(OH)₂D₃ regulates several adipogenic mediators during differentiation, proliferation and maturation of mesodermal cells into adipocytes including CCAAT/enhancer-binding proteins α, β, and γ (C/EBPα, β, and γ), C/EBPβ corepressor eight twenty-one (ETO), PPARγ/RXRα, fatty acid binding protein 4 (FABP4), lipoprotein lipase (LPL), fatty acid synthase (FASN), stearoyl-coA desaturase-1 (SCD1), glucose transporter type 4 (GLUT4) and phosphoenolpyruvate carboxykinase (PEPCK). The arrows in the figure indicate activation and blunted line indicate inhibition. The red lines and (+/−) indicate stimulatory or inhibitory effect of 1,25(OH)₂D₃ on adipogenesis dependent on the species or cellular systems studied.

Figure 3

Molecular actions of 1,25(OH)₂D₃ in inflammation and energy homeostasis in adipocytes. Stimulation via e.g., lipopolysaccharide (LPS), TNF-α via specific receptors e.g., Toll like receptor (TLR), IL-6 receptors (IL-6R) activate Nuclear factor kappa-B (NFκB) or p38 mitogen-activated protein kinase (P38MAPK) signaling dependent transcription of inflammatory genes such as interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β). 1,25(OH)₂D₃ inhibits inflammation by inhibiting Inhibitor kappa-B (IκBα) phosphorylation and translocation of NFκB as well P38MAPK into the nucleus. Furthermore, 1,25(OH)₂D₃ affects energy homeostasis. VDR^−/− mice increases energy expenditure through uncoupling proteins (UCPs). The arrows in the figure indicate activation and blunted line indicate inhibition. The red lines and arrows indicate the effect of 1,25(OH)₂D₃ on inflammatory signaling pathway.