Lim Gahyun, Jarrell Zachery R, Go Young-Mi, Jones Dean P
Nutrition and Heath Sciences, Laney Graduate School, Rollins School of Public Health, Emory University, Atlanta, GA, United States; Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA, United States.
Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA, United States.
J Nutr. 2025 Aug;155(8):2643-2652. doi: 10.1016/j.tjnut.2025.04.037. Epub 2025 May 27.
Prior research shows that amino acid metabolism plays a role in the biological processes distinguishing metabolically healthy nonobese (MHN), metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO) phenotypes. Metabolic network analysis tools are available to test for differences in amino acid associations but have not been applied to MHN, MHO, and MUO.
We aimed to characterize amino acid metabolic networks and identify key metabolic shifts distinguishing MHN, MHO, and MUO phenotypes through metabolomics and network analysis.
The plasma metabolome was analyzed by liquid chromatography with high-resolution mass spectrometry in a cross-sectional study of 213 middle-aged adults classified as MHN, MHO, or MUO based on body mass index, blood pressure, blood lipids, and blood glucose. Differential metabolic network and pathway enrichment analyses were used to measure the centrality of amino acid metabolism and associated metabolic pathways.
Partial least squares-discriminant analysis showed that amino acids were among the top discriminatory metabolites (variable importance in projection >2) for MHN, MHO, and MUO and included tryptophan (Trp), phenylalanine (Phe), tyrosine, cystine (disulfide of cysteine), alanine, glutamate, valine, and leucine/isoleucine. Network analyses with these discriminatory amino acids showed that Trp had a high network centrality in all groups, with the highest value in MHN and MHO. Phe gained centrality in obese phenotypes and became the central amino acid in MUO. Pathway enrichment analyses revealed that Phe-centered metabolic communities in obese groups (MHO and MUO) were enriched fatty acid oxidation pathways. Network and pathway analyses using all amino acids showed comparable results.
Amino acid networks differ in healthy and unhealthy obesity phenotypes, with the most central amino acid Trp in MHN and MHO shifting to Phe in MUO. Mechanistic studies are needed to determine whether increased Phe centrality is a cause or effect of metabolic dysfunctions in obesity.
先前的研究表明，氨基酸代谢在区分代谢健康的非肥胖（MHN）、代谢健康的肥胖（MHO）和代谢不健康的肥胖（MUO）表型的生物学过程中发挥作用。代谢网络分析工具可用于测试氨基酸关联的差异，但尚未应用于MHN、MHO和MUO。
我们旨在通过代谢组学和网络分析来表征氨基酸代谢网络，并识别区分MHN、MHO和MUO表型的关键代谢变化。
在一项横断面研究中，对213名中年成年人的血浆代谢组进行了液相色谱-高分辨率质谱分析，这些成年人根据体重指数、血压、血脂和血糖被分类为MHN、MHO或MUO。采用差异代谢网络和通路富集分析来衡量氨基酸代谢及相关代谢通路的中心性。
偏最小二乘判别分析表明，氨基酸是区分MHN、MHO和MUO的顶级鉴别代谢物（投影变量重要性>2）之一，包括色氨酸（Trp）、苯丙氨酸（Phe）、酪氨酸、胱氨酸（半胱氨酸的二硫化物）、丙氨酸、谷氨酸、缬氨酸和亮氨酸/异亮氨酸。对这些鉴别性氨基酸进行网络分析表明，Trp在所有组中都具有较高的网络中心性，在MHN和MHO中值最高。Phe在肥胖表型中获得中心性，并成为MUO中的中心氨基酸。通路富集分析显示，肥胖组（MHO和MUO）中以Phe为中心的代谢群落富含脂肪酸氧化通路。使用所有氨基酸进行网络和通路分析显示了可比的结果。
氨基酸网络在健康和不健康的肥胖表型中存在差异，MHN和MHO中最核心的氨基酸Trp在MUO中转变为Phe。需要进行机制研究来确定Phe中心性增加是肥胖中代谢功能障碍的原因还是结果。
