Article

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

ABSTRACT

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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    • "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.
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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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