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: 4.64). 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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    • "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 D-3, its biologically most active metabolite 1 alpha,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3), 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 D-3 intervention study, we demonstrated that all four primary VDR target genes can serve as biomarkers for the vitamin D-3 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 D-3.
    Molecular Nutrition & Food Research 10/2014; 58(10). DOI:10.1002/mnfr.201400291 · 4.91 Impact Factor
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    • "This is thus not an 'intrinsic' metabolic phenotype, it is a simple metabolic consequence of loss of insulation. Other genetically modified mice have also been shown to exhibit changes in fur and skin properties together with resistance to dietinduced obesity; these include the global knock-out of acyl coenzyme A:diacylglycerol acyltransferase 1 (DGAT1) (Smith et al., 2000; Chen et al., 2002), the global knock-out of the vitamin D receptor (Xie et al., 2002; Narvaez et al., 2009) and mice overexpressing the human apolipoprotein C1 gene (Jong et al., 1998; Jong et al., 2001). Again, it is unlikely that these modifications truly affect intrinsic metabolism; rather, the outcome is due to thermoregulatory thermogenesis. "
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    ABSTRACT: Alterations in nonshivering thermogenesis are presently discussed as being both potentially causative of and able to counteract obesity. However, the necessity for mammals to defend their body temperature means that the ambient temperature profoundly affects the outcome and interpretation of metabolic experiments. An adequate understanding and assessment of nonshivering thermogenesis is therefore paramount for metabolic studies. Classical nonshivering thermogenesis is facultative, i.e. it is only activated when an animal acutely requires extra heat (switched on in minutes), and adaptive, i.e. it takes weeks for an increase in capacity to develop. Nonshivering thermogenesis is fully due to brown adipose tissue activity; adaptation corresponds to the recruitment of this tissue. Diet-induced thermogenesis is probably also facultative and adaptive and due to brown adipose tissue activity. Although all mammals respond to injected/infused norepinephrine (noradrenaline) with an increase in metabolism, in non-adapted mammals this increase mainly represents the response of organs not involved in nonshivering thermogenesis; only the increase after adaptation represents nonshivering thermogenesis. Thermogenesis (metabolism) should be expressed per animal, and not per body mass [not even to any power (0.75 or 0.66)]. A 'cold tolerance test' does not examine nonshivering thermogenesis capacity; rather it tests shivering capacity and endurance. For mice, normal animal house temperatures are markedly below thermoneutrality, and the mice therefore have a metabolic rate and food consumption about 1.5 times higher than their intrinsic requirements. Housing and examining mice at normal house temperatures carries a high risk of identifying false positives for intrinsic metabolic changes; in particular, mutations/treatments that affect the animal's insulation (fur, skin) may lead to such problems. Correspondingly, true alterations in intrinsic metabolic rate remain undetected when metabolism is examined at temperatures below thermoneutrality. Thus, experiments with animals kept and examined at thermoneutrality are likely to yield an improved possibility of identifying agents and genes important for human energy balance.
    Journal of Experimental Biology 01/2011; 214(Pt 2):242-53. DOI:10.1242/jeb.050989 · 3.00 Impact Factor
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    ABSTRACT: Nekton Research is developing a cooperative multi-AUV system. This system, multi-AUV search array (MASA), will allow 3D searches and data collection with high spatial and temporal resolution in both inshore and near-shore environments. The paper discusses MASA's design.
    OCEANS '02 MTS/IEEE; 11/2002
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