Metabolomics Signature of Patients With Narcolepsy
Metabolomics Signature of Patients With Narcolepsy
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DOI：
10.1212/wnl.0000000000013128
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发表时间：
2022-02-01
期刊：
影响因子：
9.9
通讯作者：
Skene, Debra J.
中科院分区：
文献类型：
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作者：
Dauvilliers, Yves;Barateau, Lucie;Skene, Debra J.
背景和目的1型嗜睡综合征(Narcolepsy Type1，NT1)是一种由增食欲素神经元不可逆性破坏引起的孤儿脑部疾病。新陈代谢障碍在NT1患者中很常见，他们的身体质量指数(BMI)比一般人高10%到20%，其中三分之一是肥胖(BMI和GT；30公斤/米(2))。除了NT1中增食欲素神经元的破坏外，肥胖和非肥胖NT1患者的代谢变化尚不清楚。本研究的目的是确定NT1患者和对照组血浆代谢谱随其BMI状态的可能差异。方法我们使用目标液相色谱-质谱仪代谢组学方法，检测了117例NT1患者(包括41名肥胖者)和116名BMI匹配的对照组(包括57名肥胖者)空腹血浆中141种循环低分子代谢物，并与116名BMI匹配的对照组(包括57名肥胖者)进行比较。结果发现，无论BMI如何，NT1患者和对照组之间存在共同的代谢物，即肌氨酸、谷氨酸、去甲肉碱(C9)、5个长链溶血磷脂酰胆碱、1个鞘磷脂、12个磷脂酰胆碱和11个磷脂酰胆碱都显示出NT1中的浓度增加。受NT1(n=42)和BMI类别(n=40)显著影响的代谢产物浓度几乎没有重叠(n=5)。定量浓缩分析揭示了与正常BMI和肥胖比较中NT1/对照差异有关的共同代谢途径，即甘氨酸和丝氨酸、花生四烯酸和色氨酸代谢。驱动这些差异的代谢物是谷氨酸、肌氨酸和鸟氨酸(甘氨酸和丝氨酸代谢)；谷氨酸和PC AS C34：4(花生四烯酸代谢)；以及谷氨酸、5-羟色胺和色氨酸(色氨酸代谢)。线性代谢物-内表型回归分析表明，作为NT1代谢表型的一部分，大多数睡眠参数(即慢波睡眠时间、睡眠潜伏期和周期性腿部运动)与对照组中的代谢物浓度之间的关系丢失。讨论这些结果代表了作为BMI函数的NT1患者最全面的代谢特征，并提出了NT1的一些代谢诊断生物标志物，即谷氨酸、肌氨酸、5-羟色胺、色氨酸、去甲肉碱和一些磷脂酰胆碱。已确定的代谢途径如果得到证实，将为NT1肥胖的治疗提供可能的靶点。
Background and ObjectivesNarcolepsy type 1 (NT1) is an orphan brain disorder caused by the irreversible destruction of orexin neurons. Metabolic disturbances are common in patients with NT1 who have a body mass index (BMI) 10% to 20% higher than the general population, with one-third being obese (BMI >30 kg/m(2)). Besides the destruction of orexin neurons in NT1, the metabolic alterations in obese and nonobese patients with NT1 remain unknown. The aim of this study was to identify possible differences in plasma metabolic profiles between patients with NT1 and controls as a function of their BMI status.MethodsWe used a targeted liquid chromatography-mass spectrometry metabolomics approach to measure 141 circulating, low-molecular-weight metabolites in drug-free fasted plasma samples from 117 patients with NT1 (including 41 obese individuals) compared with 116 BMI-matched controls (including 57 obese individuals).ResultsCommon metabolites driving the difference between patients with NT1 and controls, regardless of BMI, were identified, namely sarcosine, glutamate, nonaylcarnitine (C9), 5 long-chain lysophosphatidylcholine aryls, 1 sphingolipid, 12 phosphatidylcholine diacyls, and 11 phosphatidykholine acyl-akyls, all showing increased concentrations in NT1. Metabolite concentrations significantly affected by NT1 (n = 42) and BMI category (n = 40) showed little overlap (n = 5). Quantitative enrichment analysis revealed common metabolic pathways that were implicated in the NT1/control differences in both normal BMI and obese comparisons, namely glycine and serine, arachidonic acid, and tryptophan metabolism. The metabolites driving these differences were glutamate, sarcosine, and ornithine (glycine and serine metabolism); glutamate and PC as C34:4 (arachidonic acid metabolism); and glutamate, serotonin, and tryptophan (tryptophan metabolism). Linear metabolite-endophenotype regression analyses highlight that as part of the NT1 metabolic phenotype, most of the relationships between the sleep parameters (i.e., slow-wave sleep duration, sleep latency, and periodic leg movement) and metabolite concentrations seen in the controls were lost.DiscussionThese results represent the most comprehensive metabolic profiling of patients with NT1 as a function of BMI and propose some metabolic diagnostic biomarkers for NT1, namely glutamate, sarcosine, serotonin, tryptophan, nonaylcarnitine, and some phosphatidylcholines. The metabolic pathways identified offer, if confirmed, possible targets for treatment of obesity in NT1.