Obesity associated with poor Vitamin D genes (VDR in this study) – Jan 2018

Vitamin D, Vitamin D Receptor, and Adipose Tissue: Focus on Cellular Mechanisms

Carmen J. Narvaez1, Donald G. Matthews1,2, JoEllen Welsh1
1 University at Albany, Rensselaer, NY, United States; 2 Oregon Health and Science University, Portland, OR, United States

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Table of Contents

Adipocytes function in storage of energy reserves, secretion of adipokines that regulate appetite, and control of thermogenesis. The major form of adipose tissue is termed white adipose tissue (WAT) and is located in subcutaneous and visceral depots. Development and maintenance of WAT is dependent on the nuclear receptor peroxisome prolifera- tor-activated receptor y (PPARy), which drives adipogenesis (generation of new adipocytes from mesenchymal precursors) and regulates fatty acid storage and glucose metabolism. PPARy regulates multiple target genes essential for adipocyte differentiation, lipid metabolism, and glucose homeostasis, as well as the expression of adipokines and cytokines secreted from adipose tissue. Brown adipose tissue (BAT) is a unique type of adipose tissue present in mammals that functions in body temperature regulation. Activated BAT uniquely expresses an “uncoupling protein" (UCP1) within the inner mitochondrial membrane, which uncouples substrate oxidation from ATP synthesis, leading to increased fuel oxidation and thermogenesis. The vitamin D receptor (VDR) and vitamin D-metabolizing enzymes_(CYP24A1, CYP27B1) are expressed in adipose tissue, and vitamin D signaling has been shown to alter the differentiation and phenotype of both WAT and BAT adipocytes and to modulate adiposity and energy metabolism in vivo. Examples of recently uncovered mechanisms that contribute to the effects

CONCLUSIONS AND FUTURE DIRECTIONS

In summary, adipose tissue has long been recognized as a major site of vitamin D storage, and new technologies have facilitated quantitation of the amount of vitamin D and 25(OH)D in adipose tissue depots. Although it appears likely that vitamin D storage and release is regulated (for example, during physiological states such as puberty, pregnancy, and aging), but virtually nothing is known about the mechanisms by which this might be achieved. Understanding regulatory signals and genetic determinants of vitamin D storage might provide insight into how pathological conditions such as obesity and metabolic syndrome alter the process, leading to lower serum 25(OH)D in such conditions. With respect to adipose tissue as a target for vitamin D, both mesenchymal precursors and mature adipocytes express the VDR and the major vitamin D-metabolizing enzymes [24,73,111]. Direct actions of 25(OH)D, 1,25(OH)2D, and VDR on adipogenic differentiation and gene expression have been documented, although the effects differ with model system. Animal studies support a modulatory role for dietary vitamin D and VDR activity in control of body weight, but much contradictory data exist, and detailed mechanisms are lacking. It is likely that vitamin D has distinct effects on mesenchymal precursors, preadipocytes, and mature adipocytes, which could account for much of the variability derived from in vitro studies and differences in the phenotypes of genetically engineered mice. In addition to direct effects on adipose tissue, it is quite clear that vitamin D signaling integrates pathways in different tissues (including muscle, liver, bone, and possibly brain) that influence metabolism and energy expenditure and indirectly alter the balance of lipogenesis and lipolysis in adipose tissue. Although obesity in humans is consistently associated with low serum 25(OH) D, most studies have failed to detect significant effects of vitamin D supplementation on overall body weight, although some data support beneficial effects of supplementation on fat mass, waist circumference, insulin sensitivity, and/or inflammation. As recent studies have demonstrated that vitamin D supplementation alters adipose tissue gene expression 112, and VDR has been identified as a gene induced by insulin in "healthy" obesity [113], further mechanistic research into the role of vitamin D and its receptor in adipose tissue biology is critical to resolve the current inconsistencies in this field and to facilitate translational impact.

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