Halama Anna, Horsch Marion, Kastenmüller Gabriele, Möller Gabriele, Kumar Pankaj, Prehn Cornelia, Laumen Helmut, Hauner Hans, Hrabĕ de Angelis Martin, Beckers Johannes, Suhre Karsten, Adamski Jerzy
Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Department of Physiology and Biophysics, Weill Cornell Medical College - Qatar, Doha, Qatar.
Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Arch Biochem Biophys. 2016 Jan 1;589:93-107. doi: 10.1016/j.abb.2015.09.013. Epub 2015 Sep 25.
Fat cell metabolism has an impact on body homeostasis and its proper function. Nevertheless, the knowledge about simultaneous metabolic processes, which occur during adipogenesis and in mature adipocytes, is limited. Identification of key metabolic events associated with fat cell metabolism could be beneficial in the field of novel drug development, drug repurposing, as well as for the discovery of patterns predicting obesity risk. The main objective of our work was to provide comprehensive characterization of metabolic processes occurring during adipogenesis and in mature adipocytes. In order to globally determine crucial metabolic pathways involved in fat cell metabolism, metabolomics and transcriptomics approaches were applied. We observed significantly regulated metabolites correlating with significantly regulated genes at different stages of adipogenesis. We identified the synthesis of phosphatidylcholines, the metabolism of even and odd chain fatty acids, as well as the catabolism of branched chain amino acids (BCAA; leucine, isoleucine and valine) as key regulated pathways. Our further analysis led to identification of an enzymatic switch comprising the enzymes Hmgcs2 (3-hydroxy-3-methylglutaryl-CoA synthase) and Auh (AU RNA binding protein/enoyl-CoA hydratase) which connects leucine degradation with cholesterol synthesis. In addition, propionyl-CoA, a product of isoleucine degradation, was identified as a putative substrate for odd chain fatty acid synthesis. The uncovered crosstalks between BCAA and lipid metabolism during adipogenesis might contribute to the understanding of molecular mechanisms of obesity and have potential implications in obesity prediction.
脂肪细胞代谢对身体的稳态及其正常功能有影响。然而，关于脂肪生成过程中以及成熟脂肪细胞中同时发生的代谢过程的知识是有限的。识别与脂肪细胞代谢相关的关键代谢事件在新型药物开发、药物再利用领域以及预测肥胖风险模式的发现方面可能是有益的。我们工作的主要目标是全面表征脂肪生成过程中以及成熟脂肪细胞中发生的代谢过程。为了全面确定参与脂肪细胞代谢的关键代谢途径，应用了代谢组学和转录组学方法。我们观察到在脂肪生成的不同阶段，显著调节的代谢物与显著调节的基因相关。我们确定磷脂酰胆碱的合成、偶数和奇数链脂肪酸的代谢以及支链氨基酸（BCAA；亮氨酸、异亮氨酸和缬氨酸）的分解代谢为关键调节途径。我们的进一步分析导致鉴定出一种酶开关，该开关由Hmgcs2（3-羟基-3-甲基戊二酰辅酶A合酶）和Auh（AU RNA结合蛋白/烯酰辅酶A水合酶）组成，它将亮氨酸降解与胆固醇合成联系起来。此外，异亮氨酸降解产物丙酰辅酶A被确定为奇数链脂肪酸合成的假定底物。脂肪生成过程中发现的BCAA与脂质代谢之间的相互作用可能有助于理解肥胖的分子机制，并对肥胖预测具有潜在意义。
