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

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.

Association of obesity with vitamin D deficiency and the clinical implications

“…The vitamin D receptor is expressed in both white and brown adipocytes, and vitamin D and its metabolites are stored in adipose tissue. 21 Other recent studies demonstrated that the 1,25(OH)2D3 regulated, secreted bone protein osteocalcin mediates effects on adipose tissue, β-cells, and energy metabolism. 22 Researchers have reported that vitamin D3 supplementation during weight loss did not increase weight loss or associated factors compared with placebo; however, women who became replete experienced greater improvements.…”

Vitamin D and Obesity

“…UCP1, which is a highly specific marker for brown adipocytes and mediates the dissociation of cellular respiration from energy production, was elevated more than 25-fold in VDRKO white adipocyte tissue. This elevated UCP1 coincided with a resistance to high-fat diet-induced weigh gain in VDRKO mice [63]. This study identified a novel role of VDR on lipid accumulation and gene expression in adipose tissue.…”

“…1α-hydroxylase has been reported to be expressed in adipose tissue and is functional in cultured adipocytes [62]. Interestingly, mice lacking CYP27B1 display a lean phenotype that is similar to hypoleptinemia and hyperphagia [63]. Leptin is an obesity-related gene product that is secreted by adipocytes.…”

Brown fat thermogenesis and body weight regulation in mice: relevance to humans

“…However, variation of wBAT without a corresponding variation in iBAT occurs in inbred strains of mice with spontaneous variant alleles, 20,21 in transgenic mice in which inactivation of raptor in adipocytes by Febp4-Cre recombinase (aP2-Cre) leads to induction of brown adipocytes in white fat depots, without an effect on iBAT; similarly, inactivation of the gene encoding the vitamin D receptor leads to a strong induction of uncoupling protein-1 (Ucp1) in white fat depots. 22,23 These models have provided strong evidence that mice with an elevated expression of wBAT are resistant to diet-induced obesity. Given the specificity of myf5 and PR-domain containing-16 (PRDM16) in determining the iBAT lineage, it is possible that variation in iBAT could be achieved independent of wBAT by manipulation of these genes.…”