Department of Obstetrics and Gynaecology, Medical University of Graz, Graz, Austria.
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark.
Int J Obes (Lond). 2023 Jul;47(7):529-537. doi: 10.1038/s41366-023-01295-4. Epub 2023 Apr 7.
BACKGROUND/OBJECTIVES: Obesity in pregnancy associates with changes in the glucose-insulin axis. We hypothesized that these changes affect the maternal metabolome already in the first trimester of human pregnancy and, thus, aimed to identify these metabolites.
PATIENTS/METHODS: We performed untargeted metabolomics (HPLC-MS/MS) on maternal serum (n = 181, gestational weeks 4-11). For further analysis, we included only non-smoking women as assessed by serum cotinine levels (ELISA) (n = 111). In addition to body mass index (BMI) and leptin as measures of obesity and adiposity, we metabolically phenotyped women by their fasting glucose, C-peptide and insulin sensitivity (IS index). To identify metabolites (outcome) associated with BMI, leptin, glucose, C-peptide and/or IS (exposures), we used a combination of univariable and multivariable regression analyses with multiple confounders and machine learning methods (Partial Least Squares Discriminant Analysis, Random Forest and Support Vector Machine). Additional statistical tests confirmed robustness of results. Furthermore, we performed network analyses (MoDentify package) to identify sets of correlating metabolites that are coordinately regulated by the exposures.
We detected 2449 serum features of which 277 were annotated. After stringent analysis, 15 metabolites associated with at least one exposure (BMI, leptin, glucose, C-peptide, IS). Among these, palmitoleoyl ethanolamine (POEA), an endocannabinoid-like lipid endogenously synthesized from palmitoleic acid, and N-acetyl-L-alanine were consistently associated with C-peptide in all the analyses (95% CI: 0.10-0.34; effect size: 21%; p < 0.001; 95% CI: 0.04-0.10; effect size: 7%; p < 0.001). In network analysis, most features correlating with palmitoleoyl ethanolamide and N-acetyl-L-alanine and associated with C-peptide, were amino acids or dipeptides (n = 9, 35%), followed by lipids (n = 7, 27%).
We conclude that the metabolome of pregnant women with overweight/obesity is already altered early in pregnancy because of associated changes of C-peptide. Changes of palmitoleoyl ethanolamide concentration in pregnant women with obesity-associated hyperinsulinemia may reflect dysfunctional endocannabinoid-like signalling.
背景/目的：孕期肥胖与葡萄糖-胰岛素轴的变化有关。我们假设这些变化在人类妊娠的第一个三个月就已经影响了母体代谢组，因此旨在确定这些代谢物。
患者/方法：我们对 181 名（妊娠 4-11 周）母亲的血清进行了非靶向代谢组学（HPLC-MS/MS）分析。为了进一步分析，我们仅纳入了通过血清可替宁水平（ELISA）评估的非吸烟女性（n=111）。除了体重指数（BMI）和瘦素作为肥胖和肥胖的指标外，我们还通过空腹血糖、C 肽和胰岛素敏感性（IS 指数）对女性进行了代谢表型分析。为了确定与 BMI、瘦素、葡萄糖、C 肽和/或 IS（暴露）相关的代谢物（结果），我们使用了结合单变量和多变量回归分析的方法，并考虑了多种混杂因素和机器学习方法（偏最小二乘判别分析、随机森林和支持向量机）。额外的统计检验证实了结果的稳健性。此外，我们还进行了网络分析（MoDentify 包），以确定受暴露影响的代谢物的相关物组。
我们检测到了 2449 种血清特征，其中 277 种被注释。经过严格的分析，有 15 种代谢物与至少一种暴露因素（BMI、瘦素、葡萄糖、C 肽、IS）相关。其中，棕榈油酸乙醇胺（POEA）是一种内源性的从棕榈油酸合成的内源性大麻素样脂质，以及 N-乙酰-L-丙氨酸，在所有分析中均与 C 肽一致相关（95%CI：0.10-0.34；效应大小：21%；p<0.001；95%CI：0.04-0.10；效应大小：7%；p<0.001）。在网络分析中，与棕榈油酸乙醇胺和 N-乙酰-L-丙氨酸相关且与 C 肽相关的大多数特征是氨基酸或二肽（n=9，35%），其次是脂质（n=7，27%）。
我们得出结论，超重/肥胖孕妇的代谢组在妊娠早期就已经发生了改变，这是由于 C 肽的相关变化。肥胖相关高胰岛素血症孕妇中棕榈油酸乙醇胺浓度的变化可能反映了功能失调的内源性大麻素样信号传导。
