Biomarkers of endocannabinoid system activation in severe obesity.
Biomarkers of endocannabinoid system activation in severe obesity.
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DOI：
10.1371/journal.pone.0008792
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发表时间：
2010-01-20
期刊：
影响因子：
3.7
通讯作者：
Waalen J
中科院分区：
文献类型：
--
作者：
Sipe JC;Scott TM;Murray S;Harismendy O;Simon GM;Cravatt BF;Waalen J
肥胖是一种世界性的流行病，严重的肥胖是许多疾病的危险因素，包括糖尿病、心脏病、中风和一些癌症。内源性大麻素系统（ECS）信号在大脑和外周组织中被激活，在肥胖症中起着调节体重的作用。这里的主要研究问题是血浆内源性大麻素，大麻素和相关的N-酰基乙醇胺（NAE）的定量测量，结合脂肪酸酰胺水解酶（FAAH）突变的基因分型，是否会识别严重肥胖症ECS激活的循环生物标志物。从96例体重指数（BMI）≥40 kg/m2的重度肥胖受试者和48例BMI ≤26 kg/m2的正常体重受试者中采集血浆样本。使用三重四极杆质谱法测量血浆ECS类似物。对受试者进行人类FAAH基因突变的基因分型。通过比较两组中FAAH 385次要A等位基因携带者与野生型C/C携带者的血浆ECS代谢物水平，主要分析集中在FAAH 385 C→A（P129 T）突变。主要发现是携带FAAH 385 A突变等位基因的研究受试者的平均血浆大麻素水平（15.1±1.4 pmol/ml）和相关NAE显著高于携带野生型FAAH基因型的正常受试者（13.3±1.0 pmol/ml）（p = 0.04），并且在控制BMI后保持显著性。 与野生型FAAH对照相比，在FAAH 385 A突变等位基因携带者中发现内源性大麻素anandamide和相关NAE水平显著增加。这一证据支持内源性大麻素系统激活，这是由于FAAH 385突变体A基因型对血浆AEA和相关NAE类似物的影响。这是第一项研究证明FAAH 385 A突变等位基因对人体血浆中大麻素和相关NAE水平升高有直接影响。这些生物标志物可能表明严重肥胖的风险，并可能提出新的ECS肥胖治疗策略。
Obesity is a worldwide epidemic, and severe obesity is a risk factor for many diseases, including diabetes, heart disease, stroke, and some cancers. Endocannabinoid system (ECS) signaling in the brain and peripheral tissues is activated in obesity and plays a role in the regulation of body weight. The main research question here was whether quantitative measurement of plasma endocannabinoids, anandamide, and related N-acylethanolamines (NAEs), combined with genotyping for mutations in fatty acid amide hydrolase (FAAH) would identify circulating biomarkers of ECS activation in severe obesity. Plasma samples were obtained from 96 severely obese subjects with body mass index (BMI) of ≥40 kg/m2, and 48 normal weight subjects with BMI of ≤26 kg/m2. Triple-quadrupole mass spectroscopy methods were used to measure plasma ECS analogs. Subjects were genotyped for human FAAH gene mutations. The principal analysis focused on the FAAH 385 C→A (P129T) mutation by comparing plasma ECS metabolite levels in the FAAH 385 minor A allele carriers versus wild-type C/C carriers in both groups. The main finding was significantly elevated mean plasma levels of anandamide (15.1±1.4 pmol/ml) and related NAEs in study subjects that carried the FAAH 385 A mutant alleles versus normal subjects (13.3±1.0 pmol/ml) with wild-type FAAH genotype (p = 0.04), and significance was maintained after controlling for BMI. Significantly increased levels of the endocannabinoid anandamide and related NAEs were found in carriers of the FAAH 385 A mutant alleles compared with wild-type FAAH controls. This evidence supports endocannabinoid system activation due to the effect of FAAH 385 mutant A genotype on plasma AEA and related NAE analogs. This is the first study to document that FAAH 385 A mutant alleles have a direct effect on elevated plasma levels of anandamide and related NAEs in humans. These biomarkers may indicate risk for severe obesity and may suggest novel ECS obesity treatment strategies.
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DOI：
10.1016/s1098-3597(06)80041-4
发表时间：
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期刊：
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影响因子：
--
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