Integrative Analysis of Transcriptomics, Proteomics, and Metabolomics Data of White Adipose and Liver Tissue of High-Fat Diet and Rosiglitazone-Treated Insulin-Resistant Mice Identified Pathway Alterations and Molecular Hubs
Integrative Analysis of Transcriptomics, Proteomics, and Metabolomics Data of White Adipose and Liver Tissue of High-Fat Diet and Rosiglitazone-Treated Insulin-Resistant Mice Identified Pathway Alterations and Molecular Hubs
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DOI：
10.1021/pr5005828
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发表时间：
2014-12-01
影响因子：
4.4
通讯作者：
Sauer, Sascha
中科院分区：
文献类型：
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作者：
Meierhofer, David;Weidner, Christopher;Sauer, Sascha
肥胖和2型糖尿病的发病率正在迅速增加，并已演变成全球流行病。在这项研究中，我们分析了高脂饮食（HFD）诱导的胰岛素抵抗对小鼠两个代谢靶组织——白色脂肪组织（WAT）和肝脏的分子影响。此外，我们还分析了使用特定 PPAR？的药物治疗效果。配体罗格列酮。我们整合了转录组、蛋白质组和代谢组数据集，以综合全面地了解 2 型糖尿病的分子机制。通过网络和通路分析，我们确定了 WAT 中的 SDHB 和 SUCLG1 等枢纽蛋白，以及胰岛素抵抗状态下主要代谢通路的失调，包括 TCA 循环、氧化磷酸化和支链氨基酸代谢。罗格列酮治疗主要通过 PPAR 信号传导和 WAT 中的氧化磷酸化进行调节。有趣的是，在 HFD 肝脏中，我们可以观察到参与维生素 B 代谢的蛋白质（例如 PDXDC1 和 DHFR）以及相应代谢物的减少。此外，我们可以将鞘氨醇 (Sph) 和 1-磷酸鞘氨醇 (SP1) 鉴定为肝脏中的药物特异性标记物对。总之，我们的数据表明，通过相互关联的分子途径获得生理可塑性，以抵消高热量摄入和药物治疗引起的代谢失调。
The incidences of obesity and type 2 diabetes are rapidly increasing and have evolved into a global epidemic. In this study, we analyzed the molecular effects of high-fat diet (HFD)-induced insulin-resistance on mice in two metabolic target tissues, the white adipose tissue (WAT) and the liver. Additionally, we analyzed the effects of drug treatment using the specific PPAR? ligand rosiglitazone. We integrated transcriptome, proteome, and metabolome data sets for a combined holistic view of molecular mechanisms in type 2 diabetes. Using network and pathway analyses, we identified hub proteins such as SDHB and SUCLG1 in WAT and deregulation of major metabolic pathways in the insulin-resistant state, including the TCA cycle, oxidative phosphorylation, and branched chain amino acid metabolism. Rosiglitazone treatment resulted mainly in modulation via PPAR signaling and oxidative phosphorylation in WAT only. Interestingly, in HFD liver, we could observe a decrease of proteins involved in vitamin B metabolism such as PDXDC1 and DHFR and the according metabolites. Furthermore, we could identify sphingosine (Sph) and sphingosine 1-phosphate (SP1) as a drug-specific marker pair in the liver. In summary, our data indicate physiological plasticity gained by interconnected molecular pathways to counteract metabolic dysregulation due to high calorie intake and drug treatment.