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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 and the Departments of Biomedical Sciences and Environmental Health Sciences (C.J.N., D.M., M.C., J.W.), School of Public Health, University at Albany, Rensselaer, New York 12144; Department of Biological Sciences (E.B., J.W.), University of Notre Dame, Notre Dame, Indiana 46556; and Department of Biochemistry (M.C.), Queens University, Kingston, Ontario, Canada K7L 3N6

Address all correspondence and requests for reprints to: Dr. JoEllen Welsh, Empire Innovations Professor, GenNYsis Center for Excellence in Cancer Genomics, 122G Cancer Research Center, University at Albany, Rensselaer, New York 12144. E-mail: jwelsh{at}albany.edu.

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 1-hydroxylase enzyme that generates 1,25-dihydroxyvitamin D₃, the VDR ligand. Although VDR ablation did not reduce expression of peroxisome proliferator-activated receptor- 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 D₃ and the VDR in the control of adipocyte metabolism and lipid storage in vivo.

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