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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    ABSTRACT: In addition to its principle function as a calcium regulator, vitamin D can affect cell and tissue morphology. The intestine is an important target tissue of vitamin D, as it must ensure the efficient transport of nutrients across the epithelium while excluding the passage of harmful molecules and bacteria into the organism. These functions require a highly organized morphology, which may be modified by vitamin D deficiency. To elucidate the role of vitamin D in gut morphology and barrier function, we compared the enterocyte microstructures, gut permeability, and cytoskeletal and cell junction protein expression in vitamin D receptor (VDR) knockout (KO) and wild-type (WT) mice. We found that the duodenal epithelial cells in the VDR-KO mice had longer microvilli (+19%) than those of the WT mice (P < .05). Interestingly, microvilli elongation in the VDR-KO mice was associated with higher messenger RNA and protein expression of ezrin, which is involved in the regulation of microvillus morphogenesis. Intestinal tight junction width and permeability were assessed by measuring the fluorescein isothiocyanate dextran concentrations in plasma; the concentrations were comparable between the 2 groups of mice. We further observed a decrease in the messenger RNA and protein expression of the calcium-transporting tight junction protein claudin-2 in the VDR-KO mice compared with the WT mice (P < .05). In conclusion, the mice lacking VDR had longer enterocyte microvilli, likely as a result of increased ezrin expression. However, the morphology of the tight junctions and the intestinal permeability for large molecules were not affected.
    No preview · Article · Oct 2015 · Nutrition research
    • "Results in rodent models are more supportive of an effect of VDR/ vitamin D on energy metabolism but in an opposite way to epidemiological data. Indeed, Vdr −/− mice present a lean phenotype and a resistance to high-fat (HF) diet-induced obesity [16] [17]. Such phenotype was related to an enhancement of uncoupling proteins (UCPs) in white adipose tissue and brown adipose tissue (BAT) and an induction of fatty acid β-oxidation in white adipose tissue. "
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    ABSTRACT: Prospective studies reported an inverse correlation between 25 hydroxy-vitamin D plasma levels and prevalence of obesity and type 2 diabetes. In addition, 25 hydroxy-vitamin D status may be a determinant of obesity onset. However, the causality between these observations is not yet established. We studied the preventive effect of vitamin D3 supplementation (15000 IU/kg of food for 10 weeks) on onset of obesity in a diet-induced obesity mouse model. We showed that the vitamin D3 supplementation limited weight gain induced by high-fat diet, which paralleled with an improvement of glucose homeostasis. The limitation of weight gain could further be explained by an increased of lipid oxidation, possibly due to an up-regulation of genes involved in fatty acid oxidation and mitochondrial metabolism, leading to increased energy expenditure. Altogether, these data show that vitamin D3 regulates energy expenditure, and suggest that vitamin D3 supplementation may represent a strategy of preventive nutrition to fight the onset of obesity and associated metabolic disorders.
    No preview · Article · Oct 2014 · The Journal of Nutritional Biochemistry
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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.
    Full-text · Article · Oct 2014 · Molecular Nutrition & Food Research
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