Metabolite profiling in plasma and tissues of ob/ob and db/db mice identifies novel markers of obesity and type 2 diabetes
Metabolite profiling in plasma and tissues of ob/ob and db/db mice identifies novel markers of obesity and type 2 diabetes
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DOI：
10.1007/s00125-015-3656-y
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发表时间：
2015-09-01
期刊：
影响因子：
8.2
通讯作者：
Daniel, Hannelore
中科院分区：
文献类型：
--
作者：
Giesbertz, Pieter;Padberg, Inken;Daniel, Hannelore
目的/假设人类代谢组学方法已鉴定出约 40 种与胰岛素抵抗 (IR) 和 2 型糖尿病相关的血浆代谢物，这些代谢物通常与肥胖相关。我们的目的是分离血浆中与糖尿病相关和与肥胖相关的代谢物改变，并研究代谢重要组织对血浆代谢物浓度的影响。方法研究了两种肥胖小鼠模型；一种仅患有肥胖症 (ob/ob)，另一种患有 2 型糖尿病 (db/db)。这两种模型都因瘦素信号受损而导致肥胖，但不同的遗传背景决定了对糖尿病的易感性。在这些小鼠中，我们通过半定量 GC-MS 和定量液相色谱 (LC)-MS/MS 分析了血浆、肝脏、骨骼肌和脂肪组织的多种代谢物。结果代谢物分析确定了 24 种与糖尿病特别相关但与肥胖无关的代谢物。其中包括已知的标记物，例如 1,5-脱水-d-山梨糖醇、3-羟基丁酸酯和最近报道的标记物乙醛酸盐。糖尿病模型中的新代谢物是赖氨酸、O-磷酸酪氨酸和支链脂肪酸。我们还鉴定了 33 种在两个模型中发生类似改变的代谢物，以支链氨基酸 (BCAA) 以及甘氨酸、丝氨酸、反式 4-羟脯氨酸以及各种脂质种类和衍生物为代表。相关性分析显示，与 ob/ob 小鼠相比，db/db 小鼠血浆氨基酸与脂肪组织代谢物的关联性更强，这表明脂肪组织对糖尿病状态下血浆变化的显着贡献。结论/解释通过研究具有与人类肥胖和糖尿病类似的代谢特征的小鼠，我们发现了新的代谢实体 在适当的人类群体中进行验证并揭示其可能的组织来源。
Aims/hypothesis Metabolomics approaches in humans have identified around 40 plasma metabolites associated with insulin resistance (IR) and type 2 diabetes, which often coincide with those for obesity. We aimed to separate diabetes-associated from obesity-associated metabolite alterations in plasma and study the impact of metabolically important tissues on plasma metabolite concentrations.Methods Two obese mouse models were studied; one exclusively with obesity (ob/ob) and another with type 2 diabetes (db/db). Both models have impaired leptin signalling as a cause for obesity, but the different genetic backgrounds determine the susceptibility to diabetes. In these mice, we profiled plasma, liver, skeletal muscle and adipose tissue via semi-quantitative GC-MS and quantitative liquid chromatography (LC)-MS/MS for a wide range of metabolites.Results Metabolite profiling identified 24 metabolites specifically associated with diabetes but not with obesity. Among these are known markers such as 1,5-anhydro-d-sorbitol, 3-hydroxybutyrate and the recently reported marker glyoxylate. New metabolites in the diabetic model were lysine, O-phosphotyrosine and branched-chain fatty acids. We also identified 33 metabolites that were similarly altered in both models, represented by branched-chain amino acids (BCAA) as well as glycine, serine, trans-4-hydroxyproline, and various lipid species and derivatives. Correlation analyses showed stronger associations for plasma amino acids with adipose tissue metabolites in db/db mice compared with ob/ob mice, suggesting a prominent contribution of adipose tissue to changes in plasma in a diabetic state.Conclusions/interpretation By studying mice with metabolite signatures that resemble obesity and diabetes in humans, we have found new metabolite entities for validation in appropriate human cohorts and revealed their possible tissue of origin.