Sun Xiaocun, Morris Kristin L, Zemel Michael B
University of Tennessee, Knoxville, Tenn. 37996-1900, USA.
J Nutrigenet Nutrigenomics. 2008;1(1-2):30-48. doi: 10.1159/000109873. Epub 2007 Oct 16.
Dietary calcium inhibits adiposity, and a key underlying mechanism is suppression of calcitriol, which modulates Ca(2+) signaling and mitochondrial uncoupling in adipocytes. We demonstrated that calcitriol directly regulates adipocyte 11beta-HSD-1 expression and cortisol production in human adipocytes in vitro and dietary calcium inhibits visceral adipose tissue 11beta-HSD-1 expression in mice, indicating an interaction of calcitriol and cortisol in obesity. Consequently, we have evaluated the gene expression profile of human subcutaneous adipocytes treated with calcitriol and/or cortisone. Data analysis demonstrated significant calcitriol modulation of gene expression toward inhibition of the adipocyte apoptosis (e.g., VEGF and STC-2) and promotion of adipocyte proliferation (e.g., IGF-1 and IGF-1R). Calcitriol also up-regulated oxidative stress and inflammatory genes such as NOX-4 and TLR-3. The calcitriol/cortisone combination resulted in significant additional up-regulation of 11beta-HSD-1 and down-regulation of adiponectin expression, while cortisone exerted little independent effect in the absence of calcitriol. Overall, calcitriol stimulated a pattern of adipocyte gene expression which favored adipocyte proliferation, oxidative and inflammatory stress and visceral adiposity, and these effects were amplified in the presence of cortisone; however, this conclusion must be tempered by the adipocyte source (subcutaneous) and requires confirmation in visceral adipocytes.
膳食钙可抑制肥胖，其关键潜在机制是抑制骨化三醇，骨化三醇可调节脂肪细胞中的Ca(2+)信号传导和线粒体解偶联。我们证明，骨化三醇在体外可直接调节人脂肪细胞中11β-羟类固醇脱氢酶1（11β-HSD-1）的表达和皮质醇生成，膳食钙可抑制小鼠内脏脂肪组织中11β-HSD-1的表达，这表明骨化三醇与皮质醇在肥胖过程中存在相互作用。因此，我们评估了用骨化三醇和/或可的松处理的人皮下脂肪细胞的基因表达谱。数据分析表明，骨化三醇对基因表达有显著调节作用，可抑制脂肪细胞凋亡（如血管内皮生长因子和STC-2）并促进脂肪细胞增殖（如胰岛素样生长因子1和胰岛素样生长因子1受体）。骨化三醇还上调了氧化应激和炎症相关基因，如NADPH氧化酶4（NOX-4）和Toll样受体3（TLR-3）。骨化三醇/可的松联合使用导致11β-HSD-1进一步显著上调，脂联素表达下调，而在没有骨化三醇的情况下，可的松几乎没有独立作用。总体而言，骨化三醇刺激了一种有利于脂肪细胞增殖、氧化和炎症应激以及内脏肥胖的脂肪细胞基因表达模式，并且在可的松存在的情况下这些作用会被放大；然而，这一结论必须考虑到脂肪细胞来源（皮下），并需要在内脏脂肪细胞中得到证实。
