Transomics analysis reveals allosteric and gene regulation axes for altered hepatic glucose-responsive metabolism in obesity
Transomics analysis reveals allosteric and gene regulation axes for altered hepatic glucose-responsive metabolism in obesity
复制标题
DOI：
10.1126/scisignal.aaz1236
复制
发表时间：
2020-12-01
影响因子：
7.3
通讯作者：
Kuroda, Shinya
中科院分区：
文献类型：
--
作者：
Kokaji, Toshiya;Hatano, Atsushi;Kuroda, Shinya
与肥胖相关的糖耐量受损会导致餐后高血糖，并可能导致2型糖尿病。为了研究健康和肥胖状态下肝脏代谢的差异，我们构建并分析了transomics葡萄糖响应代谢网络，其中包括健康和肥胖小鼠肝脏的代谢物，代谢酶基因，转录因子和胰岛素信号蛋白的表达数据。我们整合了口服葡萄糖后野生型和瘦素缺乏型肥胖（ob/ob）小鼠的多组学时间过程数据。在野生型小鼠中，代谢反应在口服葡萄糖给药后10分钟内迅速受到葡萄糖响应代谢物（其功能为变构调节剂和代谢酶底物）和Akt诱导的葡萄糖响应基因编码代谢酶表达变化的调节。在ob/ob小鼠中，大多数葡萄糖响应性代谢产物的快速调节不存在。相反，葡萄糖给药在碳水化合物、脂质和氨基酸代谢酶编码基因的表达中产生缓慢的变化，从而在数小时的时间尺度上改变代谢反应。在健康和肥胖小鼠中几乎没有发生调节事件。因此，我们的transomics网络分析表明，葡萄糖响应性肝脏代谢的调节是通过健康和肥胖状态下的不同机制介导的。变构调节剂和底物以及基因表达的快速变化主导健康状态，而基因表达的缓慢变化主导肥胖状态。
Impaired glucose tolerance associated with obesity causes postprandial hyperglycemia and can lead to type 2 diabetes. To study the differences in liver metabolism in healthy and obese states, we constructed and analyzed transomics glucose-responsive metabolic networks with layers for metabolites, expression data for metabolic enzyme genes, transcription factors, and insulin signaling proteins from the livers of healthy and obese mice. We integrated multiomics time course data from wild-type and leptin-deficient obese (ob/ob) mice after orally administered glucose. In wild-type mice, metabolic reactions were rapidly regulated within 10 min of oral glucose administration by glucose-responsive metabolites, which functioned as allosteric regulators and substrates of metabolic enzymes, and by Akt-induced changes in the expression of glucose-responsive genes encoding metabolic enzymes. In ob/ob mice, the majority of rapid regulation by glucose-responsive metabolites was absent. Instead, glucose administration produced slow changes in the expression of carbohydrate, lipid, and amino acid metabolic enzyme-encoding genes to alter metabolic reactions on a time scale of hours. Few regulatory events occurred in both healthy and obese mice. Thus, our transomics network analysis revealed that regulation of glucose-responsive liver metabolism is mediated through different mechanisms in healthy and obese states. Rapid changes in allosteric regulators and substrates and in gene expression dominate the healthy state, whereas slow changes in gene expression dominate the obese state.