Lean Phenotype and Resistance to Diet-Induced Obesity in Vitamin D Receptor Knockout Mice Correlates with Induction of Uncoupling Protein-1 in White Adipose Tissue

GenNYsis Center for Excellence in Cancer Genomics, 122G Cancer Research Center, University at Albany, Rensselaer, NY 12144, USA.
Endocrinology (Impact Factor: 4.5). 10/2008; 150(2):651-61. DOI: 10.1210/en.2008-1118
Source: PubMed


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. 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. 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. Regardless of genetic background, both sc and visceral white adipose tissue depots were smaller in VDRKO mice than WT mice. The lean phenotype of VDRKO mice was associated with reduced serum leptin and compensatory increased food intake. Similar effects on adipose tissue, leptin and food intake were observed in mice lacking Cyp27b1, the 1alpha-hydroxylase enzyme that generates 1,25-dihydroxyvitamin D(3), the VDR ligand. Although VDR ablation did not reduce expression of peroxisome proliferator-activated receptor-gamma or fatty acid synthase, PCR array screening identified several differentially expressed genes in white adipose tissue from WT and VDRKO mice. Uncoupling protein-1, which mediates dissociation of cellular respiration from energy production, was greater than 25-fold elevated in VDRKO white adipose tissue. Consistent with elevation in uncoupling protein-1, VDRKO mice were resistant to high-fat diet-induced weight gain. 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.

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    • "VitD and the VDR on cell size and cell shape. For example, adipocytes [4] and skeletal muscle cells [5] [6] were smaller in animal models lacking vitamin D function. In addition, substantial changes in cellular morphology could also be observed in breast cancer, prostate cancer, bronchial epithelial and dendritic cells treated with 1,25(OH) 2 D or its corresponding analogs [7] [8] [9] [10]. "

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    • "In the mouse preadipocyte model 3T3-L1, 1,25(OH) 2 D 3 inhibits adipogenesis [12] [13], and also in the human Simpson–Golabi–Behmel syndrome (SGBS) preadipocyte model, vitamin D 3 metabolites modulate the differentiation process [10] [14]. In addition, evidence for an in vivo role of VDR in adiposity was demonstrated by studies with transgenic and knockout mice [15] [16] [17]. VDR is a transcription factor [18] and member of the superfamily of nuclear receptors, many of which can be activated by small lipophilic ligands [19]. "
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    ABSTRACT: Scope: Vitamin D₃, its biologically most active metabolite 1α,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), and the vitamin D receptor (VDR) are important for adipose tissue biology. Methods and results: We extrapolated genomic VDR association loci in adipocytes from 55 conserved genome-wide VDR-binding sites in nonfat tissues. Taking the genes DUSP10, TRAK1, NRIP1, and THBD as examples, we confirmed the predicted VDR binding sites upstream of their transcription start sites and showed rapid mRNA up-regulation of all four genes in SGBS human pre-adipocytes. Using adipose tissue biopsy samples from 47 participants of a 5-month vitamin D₃ intervention study, we demonstrated that all four primary VDR target genes can serve as biomarkers for the vitamin D₃ responsiveness of human individuals. Changes in DUSP10 gene expression appear to be the most comprehensive marker, while THBD mRNA changes characterized a rather different group of study participants. Conclusion: We present a new approach to predict vitamin D target genes based on conserved genomic VDR-binding sites. Using human adipocytes as examples, we show that such ubiquitous VDR target genes can be used as markers for the individual's response to a supplementation with vitamin D₃.
    Molecular Nutrition & Food Research 10/2014; 58(10). DOI:10.1002/mnfr.201400291 · 4.60 Impact Factor
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    • "A number of studies have suggested that vitamin D has a novel role in regulating energy metabolism. The vitamin D receptor knockout (VDRKO) and the Cyp27b1 knockout (Cyp27b1KO) mice exhibit elevated energy expenditure with subsequent loss of body fat over time (Narvaez et al., 2009; Wong et al., 2011). In human adipocytes, 1,25(OH)2D3 inhibits uncoupling protein-1 expression and alters Ca2+ homeostasis, suggesting a regulatory role of vitamin D in thermogenesis and provides rationale for the observed lean phenotype in VDRKO and Cyp27b1KO mice (Xue et al., 1998; Shi et al., 2001, 2002). "
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    ABSTRACT: Epidemiological data have demonstrated an inverse association between serum vitamin D3 levels, cancer incidence and related mortality. However, the effects of vitamin D on prostate cancer biology and its utility for prevention of prostate cancer progression are not as well-defined. The data are often conflicting: some reports suggest that vitamin D3 induces apoptosis in androgen dependent prostate cancer cell lines, while others suggest that vitamin D3 only induces cell cycle arrest. Recent molecular studies have identified an extensive synergistic crosstalk between the vitamin D- and androgen-mediated mRNA and miRNA expression, adding an additional layer of post-transcriptional regulation to the known VDR- and AR-regulated gene activation. The Warburg effect, the inefficient metabolic pathway that converts glucose to lactate for rapid energy generation, is a phenomenon common to many different types of cancer. This process supports cell proliferation and promotes cancer progression via alteration of glucose, glutamine and lipid metabolism. Prostate cancer is a notable exception to this general process since the metabolic switch that occurs early during malignancy is the reverse of the Warburg effect. This "anti-Warburg effect" is due to the unique biology of normal prostate cells that harbor a truncated TCA cycle that is required to produce and secret citrate. In prostate cancer cells, the TCA cycle activity is restored and citrate oxidation is used to produce energy for cancer cell proliferation. 1,25(OH)2D3 and androgen together modulates the TCA cycle via transcriptional regulation of zinc transporters, suggesting that 1,25(OH)2D3 and androgen maintain normal prostate metabolism by blocking citrate oxidation. These data demonstrate the importance of androgens in the anti-proliferative effect of vitamin D in prostate cancer and highlight the importance of understanding the crosstalk between these two signaling pathways.
    Frontiers in Physiology 05/2014; 5:183. DOI:10.3389/fphys.2014.00183 · 3.53 Impact Factor
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