肥胖共患中枢性性早熟女童的脂质组学分析

Lipidomics analysis of childhood obesity comorbid with central precocious puberty

摘要

目的：通过脂质组学分析技术，系统筛选儿童肥胖共患中枢性性早熟（childhood obesity comorbid with central precocious puberty，CO-CPP）的潜在生物标志物，并探索差异脂质联合疾病相关临床指标应用于CO-CPP早期识别和预警的可行性，为临床实践提供新依据。方法：选取2024年1月—2025年6月首次就诊于南京医科大学附属淮安第一医院儿科内分泌门诊的6~8岁肥胖女童20例，根据是否合并中枢性性早熟（central precocious puberty，CPP）或外周性性早熟（peripheral precocious puberty，PPP）分为CO-CPP组（10例）和肥胖共患外周性性早熟（childhood obesity comorbid with peripheral precocious puberty，CO-PPP）组（10例）。比较两组一般临床资料，采集血清样本进行非靶向脂质组学分析。筛选差异脂质后开展受试者工作特征（receiver operating characteristic，ROC）曲线分析，进一步结合临床指标通过二元Logistic回归构建联合预测模型，并开展联合ROC分析评估预测效能。结果：脂质组学分析共鉴定出42种差异有统计学意义的脂质分子，其中神经酰胺（ceramide，Cer）、磷脂酰胆碱（phosphatidylcholine，PC）表达上调，磷脂酰乙醇胺（phosphatidylethanolamine，PE）表达下调。Cer、PC、PE单独预测CO-CPP的ROC曲线下面积（area under the curve，AUC）分别为0.810、0.798、0.834，均展现出良好的判别效能（P均< 0.05）。Cer联合基础黄体生成素（luteinizing hormone，LH）的预测模型AUC可达0.970。结论：CO-CPP女童体内与青春期发育相关的关键脂质Cer、PC表达上调，PE表达下调，上述脂质或可作为CO-CPP的潜在生物学标志物。Cer联合基础LH的判别效能优于单一脂质指标，具有较好的临床应用潜力。

Abstract

Objective：This study employed lipidomics analysis to systematically screen potential biomarkers of childhood obesity comorbid with central precocious puberty（CO-CPP），and explored the feasibility of combining these biomarkers with disease-related clinical indicators to provide new evidence for early identification and warning of CO-CPP. Methods：A total of 20 obese female children aged 6 to 8 years who first visited the Pediatric Endocrinology Clinic of the Affiliated Huai’an No. 1 People’s Hospital of Nanjing Medical University between January 2024 and June 2025 were enrolled. They were divided into the CO-CPP group（n=10）and the comorbidity of childhood obesity comorbid with peripheral precocious puberty（CO-PPP）group（n=10）based on the presence of central precocious puberty（CPP）or peripheral precocious puberty（PPP）. General clinical data were compared between the two groups，and serum samples were collected for non-targeted lipidomics analysis. Differential lipids were screened using receiver operating characteristic（ROC）curve analysis，and a combined predictive model was constructed with clinical indicators via binary logistic regression，followed by further combined ROC analysis. Results：Lipidomics analysis identified 42 lipid molecules with significant differences. Among them，the expression of ceramide（Cer）and phosphatidylcholine（PC）were up-regulated，while the expression of phosphatidylethanolamine（PE）was down-regulated. The area under the curve（AUC）of ROC for predicting CO-CPP by Cer，PC，and PE alone was 0.810，0.798，and 0.834，respectively，all of which showed good discriminative efficacy（all P<0.05）. The AUC of the combined prediction model of Cer and the basal level of luteinizing hormone（LH）was 0.970. Conclusion：In girls with CPP，the expressions of Cer and PC，the key lipids associated with pubertal development，are up-regulated，while the expression of PE is down-regulated. These lipids may serve as potential biological markers for CPP. The discriminative efficacy of Cer combined with basal LH is superior to that of single lipid indicators，showing good potential for clinical application.

关键词

肥胖 / 性早熟 / 共病 / 脂质组学 / 儿童

Key words

obesity / precocious puberty / comorbidity / lipidomics / children

参考文献

[1] BUSEBEE B, GHUSN W, CIFUENTES L, et al. Obesity：a review of pathophysiology and classification[J]. Mayo Clin Proc, 2023, 98(12):1842-1857

[2] KOSKINAS K C, VAN CRAENENBROECK E M, ANTONIADES C, et al. Obesity and cardiovascular disease：an ESC clinical consensus statement[J]. Eur J Prev Cardiol, 2025, 32(3):184-220

[3] SAEED S, BONNEFOND A, FROGUEL P. Obesity：exploring its connection to brain function through genetic and genomic perspectives[J]. Mol Psychiatry, 2025, 30(2):651-658

[4] ZHANG M R, WARD J, STRAWBRIDGE R J, et al. How do lifestyle factors modify the association between genetic predisposition and obesity—related phenotypes? A 4—way decomposition analysis using UK Biobank[J]. BMC Med, 2024, 22(1):230

[5] ZELJKOVIC A, VEKIC J, STEFANOVIC A. Obesity and dyslipidemia in early life：impact on cardiometabolic risk[J]. Metabolism, 2024, 156:155919

[6] HUANG J S, GAO C, XIAO W Q, et al. Association of childhood obesity with pubertal development in boys：a systematic review and meta—analysis[J]. Obes Rev, 2025, 26(3):e13869

[7] SHI L, JIANG Z Y, ZHANG L. Childhood obesity and central precocious puberty[J]. Front Endocrinol, 2022, 13:1056871

[8] GANMAA D, BROMAGE S, KHUDYAKOV P, et al. Influence of vitamin D supplementation on growth，body composition，and pubertal development among school—aged children in an area with a high prevalence of vitamin D deficiency：a randomized clinical trial[J]. JAMA Pediatr, 2023, 177(1):32-41

[9] WANG G Y, RADOVICK S, BUCKLEY J P, et al. Plasma insulin concentration in newborns and children and age at menarche[J]. Diabetes Care, 2023, 46(6):1231-1238

[10] CHEN X L, XIAO Z N, CAI Y L, et al. Hypothalamic mechanisms of obesity—associated disturbance of hypothalamic—pituitary—ovarian axis[J]. Trends Endocrinol Metab, 2022, 33(3):206-217

[11] ZANG S L, YIN X Q, LI P. FTO—mediated m ⁶A demethylation regulates GnRH expression in the hypothalamus via the PLCβ3/Ca ²⁺/CAMK signalling pathway[J]. Commun Biol, 2023, 6(1):1297

[12] GAO S Y, XIA L N, JIANG C, et al. Exploring the molecular mechanism of EGCG in preventing obesity—induced precocious puberty based on serum metabolomics and molecular docking[J]. Front Nutr, 2025, 12:1675535

[13] BANGALORE KRISHNA K, FUQUA J S, ROGOL A D, et al. Use of gonadotropin—releasing hormone analogs in children：update by an international consortium[J]. Horm Res Paediatr, 2019, 91(6):357-372

[14] SAHA D, KANJILAL P, KAUR M, et al. Transforming cancer diagnostics：the emergence of liquid biopsy and epigenetic markers[J]. Med Comm, 2025, 6(9):e70388

[15] ZHU Y W, SHUTTA K H, HUANG T Y, et al. Persistent PTSD symptoms are associated with plasma metabolic alterations relevant to long—term health：a metabolome—wide investigation in women[J]. Psychol Med, 2025, 55:e30

[16] SUN Y W, LIU W J, SU M, et al. Purine salvage—associated metabolites as biomarkers for early diagnosis of esophageal squamous cell carcinoma：a diagnostic model—based study[J]. Cell Death Discov, 2024, 10(1):139

[17] HUANG Y, SULEK K, STINSON S E, et al. Lipid profiling identifies modifiable signatures of cardiometabolic risk in children and adolescents with obesity[J]. Nat Med, 2025, 31(1):294-305

[18] MALARVANNAN M, SABAVATH B T N, GADDAM V, et al. Transformative potentials，challenges and innovative solutions of lipidomics in multiple clinical applications[J]. Talanta, 2025, 291:127855

[19] 中华医学会儿科学分会内分泌遗传代谢学组, 中华儿科杂志编辑委员会. 中枢性性早熟诊断与治疗专家共识（2022）[J]. 中华儿科杂志, 2023, 61(1):16-22

[20] Endocrine，Genetic and Metabolic Group of the Pediatrics Branch of the Chinese Medical Association，Editorial Board of Chinese Journal of Pediatrics. Expert consensus on diagnosis and treatment of central precocious puberty（2022）[J]. Chinese Journal of Pediatrics, 2023, 61(1):16-22

[21] LÓPEZ M, DIÉGUEZ C, TENA—SEMPERE M, et al. Ceramides in the central control of metabolism[J]. Trends Endocrinol Metab, 2025, 36(1):11-14

[22] HERAS V, CASTELLANO J M, FERNANDOIS D, et al. Central ceramide signaling mediates obesity—induced precocious puberty[J]. Cell Metab, 2020, 32(6):951-966

[23] KIM E, JEON S. The impact of phytochemicals in obesity—related metabolic diseases：focus on ceramide metabolism[J]. Nutrients, 2023, 15(3):703

[24] SINDHU S, LEUNG Y H, AREFANIAN H, et al. Neutral sphingomyelinase—2 and cardiometabolic diseases[J]. Obes Rev, 2021, 22(8):e13248

[25] FLORES GOMEZ D, BEKKERING S, TER HORST R, et al. The effect of leptin on trained innate immunity and on systemic inflammation in subjects with obesity[J]. J Leukoc Biol, 2024, 115(2):374-384

[26] JACOBO—TOVAR E, MEDEL—SÁNCHEZ A, DURÁN—CASTILLO C, et al. Insulin resistance in cancer risk and prognosis[J]. Semin Cancer Biol, 2025, 114:73-87

[27] SETHI J K, HOTAMISLIGIL G S. Metabolic messengers：tumour necrosis factor[J]. Nat Metab, 2021, 3(10):1302-1312

[28] HILDEBRANDT X, IBRAHIM M, PELTZER N. Cell death and inflammation during obesity：“Know my methods，WAT（son）”[J]. Cell Death Differ, 2023, 30(2):279-292

[29] ZEMSKI—BERRY K A, GARFIELD A, JAMBAL P, et al. Oxidised phosphatidylcholine induces sarcolemmal ceramide accumulation and insulin resistance in skeletal muscle[J]. Diabetologia, 2024, 67(12):2819-2832

[30] BŁACHNIO—ZABIELSKA A U, ROSZCZYC—OWSIEJCZUK K, IMIERSKA M, et al. CerS1 but not CerS5 gene silencing，improves insulin sensitivity and glucose uptake in skeletal muscle[J]. Cells, 2022, 11(2):206

[31] DENIMAL D, BERGAS V, PAIS—DE—BARROS J P, et al. Liraglutide reduces plasma dihydroceramide levels in patients with type 2 diabetes[J]. Cardiovasc Diabetol, 2023, 22(1):104

[32] SERGI D, ZAULI E, CELEGHINI C, et al. Ceramides as the molecular link between impaired lipid metabolism，saturated fatty acid intake and insulin resistance：are all saturated fatty acids to be blamed for ceramide—mediated lipotoxicity?[J]. Nutr Res Rev, 2025, 38(1):256-266

[33] YANG J Y, ZHANG T T, DONG Z, et al. Dietary supplementation with exogenous sea—cucumber—derived ceramides and glucosylceramides alleviates insulin resistance in high—fructose—diet—fed rats by upregulating the IRS/PI3K/Akt signaling pathway[J]. J Agric Food Chem, 2021, 69(32):9178-9187

[34] HAMMERSCHMIDT P, BRÜNING J C. Contribution of specific ceramides to obesity—associated metabolic diseases[J]. Cell Mol Life Sci, 2022, 79(8):395

[35] GRAPENTINE S, SINGH R K, BAKOVIC M. Skeletal muscle consequences of phosphatidylethanolamine synthesis deficiency[J]. Function（Oxf）, 2023, 4(4):zqad020

[36] STACHOWICZ K. Deciphering the mechanisms of reciprocal regulation or interdependence at the cannabinoid CB1 receptors and cyclooxygenase—2 level：effects on mood，cognitive implications，and synaptic signaling[J]. Neurosci Biobehav Rev, 2023, 155:105439

[37] MARINO M, D’AURIA R, MELE E, et al. The interplay between kisspeptin and endocannabinoid systems modulates male hypothalamic and gonadic control of reproduction in vivo [J]. Front Endocrinol, 2023, 14:1269334

[38] XIE Q Y, KANG Y F, ZHANG C L, et al. The role of kisspeptin in the control of the hypothalamic—pituitary—gonadal axis and reproduction[J]. Front Endocrinol, 2022, 13:925206

[39] ZHANG Y R, LIU Y X, SUN J, et al. Arachidonic acid metabolism in health and disease[J]. Med Comm, 2023, 4(5):e363

[40] LANGE T, DEPMEIER T, STRÜNKER T, et al. HPLC fluorescence assay for measuring the activity of NAPE—PLD and the action of inhibitors affecting this enzyme[J]. J Pharm Biomed Anal, 2023, 229:115354

基金资助

江苏省妇幼保健协会科研基金(FYX202213)