Kaburagi Tomoko, Kizuka Yasuhiko, Kitazume Shinobu, Taniguchi Naoyuki
From the Department of Health Science, Faculty of Sports and Health Sciences, Daito Bunka University, Higashi-Matsuyama, Saitama 355-8681, Japan and
the Disease Glycomics Team, Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Center for Systems Chemical Biology, Global Research Cluster, RIKEN, Wako, Saitama 351-0198, Japan.
J Biol Chem. 2017 Feb 10;292(6):2278-2286. doi: 10.1074/jbc.M116.747667. Epub 2016 Dec 28.
Adipose tissue plays critical roles in obesity and related diseases such as diabetes and cardiovascular diseases. Previous reports suggest that glycans, the most common posttranslational modifications, are involved in obesity-related diseases, but what type of glycan regulates adipogenesis during obesity remains unclear. In this study, we first quantified the mRNA levels of 167 genes (encoding 144 glycosyltransferases and 23 related enzymes) in visceral adipose tissues (VATs) from control mice and high-fat diet (HFD)-induced obese mice. We found that a gene encoding β-galactoside α2,6-sialyltransferase-1 (), a key enzyme responsible for the biosynthesis of α2,6-linked sialic acid in -linked glycans, was most down-regulated in VATs from obese mice. We confirmed the reduction in α2,6-sialic acid in VATs from obese mice and differentiated adipocyte model 3T3-L1 cells. Using proteomic analysis, integrin-β1 was identified as one of the target α2,6-sialylated proteins in adipose tissues, and phosphorylation of its downstream molecule focal adhesion kinase was found to be decreased after HFD feeding. overexpression in differentiating 3T3-L1 cells inhibited adipogenesis with increased phosphorylation of focal adhesion kinase. Furthermore, knockout mice exhibited increased bodyweight and VAT weight after HFD feeding. The down-regulation of during adipogenesis was canceled by treatment with a DNA methyltransferase inhibitor, suggesting an involvement of epigenetic DNA methylation in silencing. Our findings suggest that ST6GAL1 has an inhibitory role in adipogenesis through integrin-β1 activation, providing new insights into the roles and regulation mechanisms of glycans in adipocytes during obesity.
脂肪组织在肥胖及相关疾病（如糖尿病和心血管疾病）中起着关键作用。先前的报道表明，聚糖作为最常见的翻译后修饰，与肥胖相关疾病有关，但在肥胖过程中何种类型的聚糖调节脂肪生成仍不清楚。在本研究中，我们首先对来自对照小鼠和高脂饮食（HFD）诱导的肥胖小鼠的内脏脂肪组织（VATs）中167个基因（编码144种糖基转移酶和23种相关酶）的mRNA水平进行了定量。我们发现，编码β-半乳糖苷α2,6-唾液酸转移酶-1（ST6GAL1）的基因，一种负责在N-连接聚糖中生物合成α2,6-连接唾液酸的关键酶，在肥胖小鼠的VATs中下调最为明显。我们证实了肥胖小鼠的VATs和分化的脂肪细胞模型3T3-L1细胞中α2,6-唾液酸的减少。通过蛋白质组学分析，整合素-β1被鉴定为脂肪组织中α2,6-唾液酸化的靶蛋白之一，并且发现高脂饮食喂养后其下游分子粘着斑激酶的磷酸化减少。在分化的3T3-L1细胞中过表达ST6GAL1抑制脂肪生成，同时粘着斑激酶的磷酸化增加。此外，ST6GAL1基因敲除小鼠在高脂饮食喂养后体重和VAT重量增加。脂肪生成过程中ST6GAL1的下调通过DNA甲基转移酶抑制剂处理而被消除，这表明表观遗传DNA甲基化参与了ST6GAL1的沉默。我们的研究结果表明，ST6GAL1通过整合素-β1激活对脂肪生成具有抑制作用，为肥胖期间聚糖在脂肪细胞中的作用和调节机制提供了新的见解。
