Global transcriptome profiling identifies KLF15 and SLC25A10 as modifiers of adipocytes insulin sensitivity in obese women.
Global transcriptome profiling identifies KLF15 and SLC25A10 as modifiers of adipocytes insulin sensitivity in obese women.
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DOI：
10.1371/journal.pone.0178485
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Dahlman I
中科院分区：
文献类型：
--
作者：
Kulyté A;Ehrlund A;Arner P;Dahlman I
虽然肥胖与胰岛素抵抗（IR）和2型糖尿病（T2D）的联系机制尚未完全了解，但很可能涉及脂肪组织功能的改变。本研究的目的是确定新的基因控制脂肪细胞胰岛素敏感性肥胖妇女无论是胰岛素抵抗（OIR）或敏感（OIS）脂肪细胞。在一项大型观察性研究中，首先通过测量来自腹部皮下白色脂肪组织（WAT）的分离脂肪细胞中的脂肪生成来确定胰岛素敏感性。在葡萄糖转运为限速步骤的条件下测量脂肪生成，并反映体内胰岛素敏感性。然后，我们进行了基于微阵列的转录组分析的皮下WAT标本从一个亚组的9瘦，21 OIS和18肥胖OIR妇女。我们可以鉴定出OIR和OIS组之间差异表达的432个基因（FDR ≤5%）。这些基因在与葡萄糖和氨基酸代谢、细胞呼吸和胰岛素信号传导相关的途径中富集，并且包括诸如SLC2A4、AKT2的基因以及编码线粒体呼吸链中的酶的基因。两个IR相关基因，KLF15编码的转录因子和SLC25A10编码的二羧酸载体，被选择在体外分化的脂肪细胞的功能评价。使用siRNA敲低KLF15和SLC25A10抑制胰岛素刺激的脂肪细胞脂肪生成。siRNA处理的细胞的转录组分析表明，KLF15可能通过影响PPARG，PXMP2，AQP7，LPL和线粒体呼吸链基因的表达来控制胰岛素敏感性。SLC25A10的敲除对转录组仅具有适度的影响，这表明由于其在脂肪酸合成中的重要作用，其可能独立于转录而直接影响脂肪细胞中的胰岛素敏感性。总之，这项研究确定了与肥胖无关的女性脂肪细胞中胰岛素敏感性相关的新基因。KFL15和SLC25A10是在葡萄糖转运是限速步骤的条件下胰岛素刺激的脂肪生成的抑制剂。
Although the mechanisms linking obesity to insulin resistance (IR) and type 2 diabetes (T2D) are not entirely understood, it is likely that alterations of adipose tissue function are involved. The aim of this study was to identify new genes controlling insulin sensitivity in adipocytes from obese women with either insulin resistant (OIR) or sensitive (OIS) adipocytes. Insulin sensitivity was first determined by measuring lipogenesis in isolated adipocytes from abdominal subcutaneous white adipose tissue (WAT) in a large observational study. Lipogenesis was measured under conditions where glucose transport was the rate limiting step and reflects in vivo insulin sensitivity. We then performed microarray-based transcriptome profiling on subcutaneous WAT specimen from a subgroup of 9 lean, 21 OIS and 18 obese OIR women. We could identify 432 genes that were differentially expressed between the OIR and OIS group (FDR ≤5%). These genes are enriched in pathways related to glucose and amino acid metabolism, cellular respiration, and insulin signaling, and include genes such as SLC2A4, AKT2, as well as genes coding for enzymes in the mitochondria respiratory chain. Two IR-associated genes, KLF15 encoding a transcription factor and SLC25A10 encoding a dicarboxylate carrier, were selected for functional evaluation in adipocytes differentiated in vitro. Knockdown of KLF15 and SLC25A10 using siRNA inhibited insulin-stimulated lipogenesis in adipocytes. Transcriptome profiling of siRNA-treated cells suggested that KLF15 might control insulin sensitivity by influencing expression of PPARG, PXMP2, AQP7, LPL and genes in the mitochondrial respiratory chain. Knockdown of SLC25A10 had only modest impact on the transcriptome, suggesting that it might directly influence insulin sensitivity in adipocytes independently of transcription due to its important role in fatty acid synthesis. In summary, this study identifies novel genes associated with insulin sensitivity in adipocytes in women independently of obesity. KFL15 and SLC25A10 are inhibitors of insulin-stimulated lipogenesis under conditions when glucose transport is the rate limiting step.