Department of Pediatrics, University of California at San Diego , La Jolla, California.
Department of Medicine, University of California at San Diego , La Jolla, California.
Physiol Genomics. 2018 Mar 1;50(3):144-157. doi: 10.1152/physiolgenomics.00045.2017. Epub 2018 Jan 8.
Highly inbred C57BL/6 mice show wide variation in their degree of insulin resistance in response to diet-induced obesity even though they are almost genetically identical. Here we employed transcriptional profiling by RNA sequencing (RNA-Seq) of visceral adipose tissue (VAT) and liver in young mice to determine how gene expression patterns correlate with the later development of high-fat diet (HFD)-induced insulin resistance in adulthood. To accomplish this goal, we partially removed and banked tissues from pubertal mice. Mice subsequently received HFD followed by metabolic phenotyping to identify two well-defined groups of mice with either severe or mild insulin resistance. The remaining tissues were collected at study termination. We then applied RNA-Seq to generate transcriptome profiles associated with worsened insulin resistance before and after the initiation of HFD. We found 244 up- and 109 downregulated genes in VAT of the most insulin-resistant mice even before HFD exposure. Downregulated genes included serine protease inhibitor, major urinary protein, and complement genes; upregulated genes represented mostly muscle constituents. These gene families were also differentially expressed in VAT of mice with high or low insulin resistance after HFD. Inflammatory genes predicted insulin resistance in liver, but not in VAT. In contrast, when we compared VAT of all mice before and after HFD, differentially expressed genes were predominantly composed of immune response genes. These data show a distinct set of gene transcripts in young mice correlates with the severity of insulin resistance in adulthood, providing insight into the pathogenesis of insulin resistance in early life.
高度近交的 C57BL/6 小鼠在对饮食诱导肥胖的胰岛素抵抗程度上存在广泛的差异，尽管它们在基因上几乎完全相同。在这里，我们采用 RNA 测序 (RNA-Seq) 对内脏脂肪组织 (VAT) 和肝脏进行转录组谱分析，以确定基因表达模式如何与成年后高脂肪饮食 (HFD) 诱导的胰岛素抵抗的发展相关。为了实现这一目标，我们从小鼠青春期时部分切除和储存组织。随后，小鼠接受 HFD，并进行代谢表型分析，以确定具有严重或轻度胰岛素抵抗的两组小鼠。研究结束时收集剩余的组织。然后，我们应用 RNA-Seq 生成与 HFD 开始前后胰岛素抵抗恶化相关的转录组谱。我们发现，即使在暴露于 HFD 之前，最胰岛素抵抗的小鼠的 VAT 中有 244 个上调和 109 个下调基因。下调基因包括丝氨酸蛋白酶抑制剂、主要尿蛋白和补体基因；上调基因主要代表肌肉成分。这些基因家族在 HFD 后胰岛素抵抗高或低的小鼠的 VAT 中也有差异表达。炎症基因可预测肝脏胰岛素抵抗，但不能预测 VAT。相比之下，当我们比较 HFD 前后所有小鼠的 VAT 时，差异表达的基因主要由免疫反应基因组成。这些数据表明，年轻小鼠中一组独特的基因转录物与成年后胰岛素抵抗的严重程度相关，为生命早期胰岛素抵抗的发病机制提供了深入了解。
