In our previous studies, the atrophy of the mammary adipose tissue in VDRKO mice developed despite normalization of calcium homeostasis with a high-calcium rescue diet and was significantly aggravated with age ( 15). A stimulatory effect of vitamin D signaling on adipocyte differentiation was supported by the demonstration that VDR knockdown in 3T3-L1 cells inhibited adipogenesis ( 11).Ĭonsistent with the in vitro data supporting enhancement of adipogenesis by 1,25(OH) 2D 3, VDR knockout (VDRKO) mice displayed atrophy of adipose tissue surrounding the prostate and mammary glands ( 14, 15). In ex vivo cultures of bone marrow mesenchymal cells, 1,25(OH) 2D 3 enhanced the recruitment of bipotential progenitors capable of differentiation along the adipogenic and osteogenic lineages ( 13), suggesting that vitamin D signaling may coordinately enhance both osteogenesis and adipogenesis. In human adipocytes, low concentrations of 1,25(OH) 2D 3 inhibited, and VDR knockdown enhanced, the expression of uncoupling protein (ucp)-2, a member of the uncoupling protein family involved in thermogenesis, energy metabolism and obesity ( 12). These discrepancies likely reflect the distinct model systems used as well as different ligand concentrations because dose-response studies indicated that 1,25(OH) 2D 3 stimulated adipogenesis at low concentrations but inhibited differentiation and induced apoptosis at high concentrations ( 8, 12). Both stimulation and inhibition of adipogenesis by 1,25(OH) 2D 3 have been reported in cell culture models, including 3T3-L1 cells ( 7, 8, 9, 10, 11). However, the impact of the VDR and its ligand 1,25-dihydroxyvitamin D 3 on adipocyte biology remains unclear. The vitamin D receptor (VDR), another nuclear receptor that dimerizes with RXRα, is expressed in adipose tissue in vivo and is dynamically up-regulated during adipogenic differentiation in vitro ( 4, 5, 6). Studies in mutant mice also demonstrated critical roles for other RXR interacting partners, such as the liver X receptor and the thyroid hormone receptor, in adipocyte biology ( 2, 3). For example, mice with adipose-specific ablation of retinoid X receptor (RXR)-α, a heterodimer partner for PPARγ, display impaired adipogenesis and resistance to high fat diet-induced obesity ( 1). Whereas it is clear that the peroxisome proliferator-activated receptor (PPAR)-γ is an essential regulator of adipogenesis, emerging studies have implicated additional nuclear receptors in the maintenance of adiposity. Collectively, these studies identify a novel role for 1,25-dihydroxyvitamin D 3 and the VDR in the control of adipocyte metabolism and lipid storage in vivo. Consistent with elevation in uncoupling protein-1, VDRKO mice were resistant to high-fat diet-induced weight gain. Uncoupling protein-1, which mediates dissociation of cellular respiration from energy production, was greater than 25-fold elevated in VDRKO white adipose tissue. Although VDR ablation did not reduce expression of peroxisome proliferator-activated receptor-γ or fatty acid synthase, PCR array screening identified several differentially expressed genes in white adipose tissue from WT and VDRKO mice. Similar effects on adipose tissue, leptin and food intake were observed in mice lacking Cyp27b1, the 1α-hydroxylase enzyme that generates 1,25-dihydroxyvitamin D 3, the VDR ligand. The lean phenotype of VDRKO mice was associated with reduced serum leptin and compensatory increased food intake. Regardless of genetic background, both sc and visceral white adipose tissue depots were smaller in VDRKO mice than WT mice. Here we monitored body fat depots, food intake, metabolic factors, and gene expression in WT and VDRKO mice on the C57BL6 and CD1 genetic backgrounds. In previous studies, we noted that 18-month-old normocalcemic vitamin D receptor (VDR) knockout (VDRKO) mice exhibited atrophy of the mammary adipose compartment relative to wild-type (WT) littermates, suggesting a role for VDR in adiposity. Increased adiposity is a feature of aging in both mice and humans, but the molecular mechanisms underlying age-related changes in adipose tissue stores remain unclear.
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