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
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
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DOI：
10.1210/en.2008-1118
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发表时间：
2009-02-01
期刊：
影响因子：
4.8
通讯作者：
Welsh, JoEllen
中科院分区：
文献类型：
--
作者：
Narvaez, Carmen J.;Matthews, Donald;Welsh, JoEllen
在老鼠和人类中，肥胖增加都是衰老的一个特征，但与年龄相关的脂肪组织储存变化背后的分子机制尚不清楚。在以前的研究中，我们注意到18个月大的正常钙血型维生素D受体(VDR)基因敲除(VDRKO)的小鼠表现出相对于野生型(WT)小鼠乳房脂肪室的萎缩，这表明VDR在肥胖中起到了作用。在这里，我们监测了WT和VDRKO小鼠在C57BL6和CD1遗传背景下的体脂储存、食物摄入量、代谢因素和基因表达。不考虑遗传背景，VDRKO小鼠的sc和内脏白色脂肪组织库都比wt小鼠小。VDRKO小鼠的瘦肉表型与血清瘦素降低和代偿性摄食量增加有关。在缺乏Cyp27b1的小鼠身上也观察到了类似的对脂肪组织、瘦素和食物摄入量的影响。Cyp27b1是一种产生VDR配体1，25-二羟基维生素D-3的1α-羟基酶。尽管VDR消融并没有减少过氧化体增殖物激活的受体-伽马或脂肪酸合成酶的表达，但聚合酶链式反应阵列筛选发现了WT和VDRKO小鼠白色脂肪组织中的几个差异表达基因。解偶联蛋白-1介导细胞呼吸与能量产生的解离，在VDRKO白色脂肪组织中高出25倍以上。与解偶联蛋白-1的升高一致，VDRKO小鼠对高脂饮食诱导的体重增加具有抵抗力。总而言之，这些研究确定了1，25-二羟基维生素D3和VDR在体内控制脂肪细胞代谢和脂肪储存方面的新作用。(内分泌学150：651-661,2009)
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 alpha-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 D3 and the VDR in the control of adipocyte metabolism and lipid storage in vivo. (Endocrinology 150: 651-661, 2009)