CONTEXT Pubertal girls with higher total body fat (TBF) demonstrate higher androgen levels. The cause of this association is unknown but is hypothesized to relate to insulin resistance. OBJECTIVE To investigate the association between higher TBF and higher androgens in pubertal girls using untargeted metabolomics. METHODS Serum androgens were determined using a quantitative mass spectrometry-based assay. Metabolomic samples were analyzed using liquid chromatography high-resolution mass spectrometry. Associations between TBF or BMI Z-score (exposure) and metabolomic features (outcome) and between metabolomic features (exposure) and serum hormones (outcome) were examined using gaussian generalized estimating equation models with the outcome lagged by one study visit. Benjamini-Hochberg false discovery rate (FDR) adjusted p-values were calculated to account for multiple testing. RaMP-DB (Relational database of Metabolomic Pathways) was used to conduct enriched pathway analyses among features nominally associated with body composition or hormones. RESULTS Sixty-six pubertal, pre-menarchal girls (aged 10.9 ± 1.39 SD years; 60% White, 24% Black, 16% Other; 63% normal weight, 37% overweight/obese) contributed an average of 2.29 blood samples. BMI and TBF were negatively associated with most features including raffinose (a plant trisaccharide) and several bile acids. For BMI, RaMP-DB identified many enriched pathways related to bile acids. Androstenedione also showed strong negative associations with raffinose and bile acids. CONCLUSIONS Metabolomic analyses of samples from pubertal girls did not identify an insulin resistance signature to explain the association between higher TBF and androgens. Instead, we identified potential novel signaling pathways that may involve raffinose or bile acid action at the adrenal gland.

中文翻译：

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超重/肥胖的青春期女孩雄激素水平较高——代谢组学可以告诉我们原因吗？

背景 全身脂肪 (TBF) 较高的青春期女孩表现出较高的雄激素水平。这种关联的原因尚不清楚，但推测与胰岛素抵抗有关。目的 使用非靶向代谢组学研究青春期女孩较高的 TBF 与较高的雄激素之间的关联。方法 使用基于定量质谱的测定法测定血清雄激素。使用液相色谱高分辨率质谱分析代谢组样品。使用高斯广义估计方程模型检查 TBF 或 BMI Z 分数（暴露）与代谢组学特征（结果）之间以及代谢组学特征（暴露）与血清激素（结果）之间的关联，结果滞后于一次研究访视。计算 Benjamini-Hochberg 错误发现率 (FDR) 调整后的 p 值以考虑多重测试。RaMP-DB（代谢组学途径关系数据库）用于对名义上与身体成分或激素相关的特征进行丰富的途径分析。结果 66 名青春期初潮前女孩（年龄 10.9 ± 1.39 SD 岁；60% 白人，24% 黑人，16% 其他；63% 正常体重，37% 超重/肥胖）平均贡献了 2.29 个血液样本。BMI 和 TBF 与大多数特征呈负相关，包括棉子糖（一种植物三糖）和几种胆汁酸。对于 BMI，RaMP-DB 确定了许多与胆汁酸相关的富集途径。雄烯二酮还表现出与棉子糖和胆汁酸的强烈负相关。结论 对青春期女孩样本的代谢组学分析并未发现胰岛素抵抗特征来解释较高的 TBF 与雄激素之间的关联。相反，我们发现了潜在的新信号传导途径，可能涉及肾上腺的棉子糖或胆汁酸作用。