Placental LEP Promoter Hypomethylation is Associated with Increased Leptin and Umbilical Artery Vascular Resistance in Maternal Obesity
Abstract
BACKGROUND: Maternal obesity has been associated with altered fetal development involving metabolic, hormonal, vascular, and epigenetic processes. The leptin (LEP) gene is crucial for placental angiogenesis and fetal growth. However, evidence linking placental LEP promoter methylation status with both leptin levels and umbilical artery vascular resistance in the context of maternal obesity remains limited. Therefore, this study was conducted to investigate the association of placental LEP promoter hypomethylation with increased leptin levels and umbilical artery vascular resistance in maternal obesity.
METHODS: A cross-sectional study was conducted in 35 obese and 35 normal-body mass index (BMI) pregnant women delivering at term. Genomic DNA was extracted from placental tissue for the placental LEP promoter methylation examination using bisulfite conversion and CpG pyrosequencing. Umbilical artery systolic/diastolic (S/D) ratio was measured by Doppler ultrasonography, and umbilical cord leptin levels were analyzed from umbilical cord blood using enzyme-linked immunosorbent assay (ELISA).
RESULTS: Total LEP promoter methylation did not differ significantly between groups (p=0.252), but five CpG sites (CpG 5, 11, 13, 16, and 17) showed significant hypomethylation in the obesity group. Umbilical cord leptin levels were significantly higher in infants of obese mothers (p=0.002). The S/D ratio was also significantly higher in the obesity group (p<0.001), indicating increased placental vascular resistance. Maternal age, parity, and gestational age were comparable between groups.
CONCLUSION: Placental LEP promoter hypomethylation at specific CpG sites (CpG 5, 11, 13, 16, and 17) in maternal obesity is associated with increased leptin levels and elevated umbilical artery vascular resistance, suggesting a potential epigenetic mechanism linking maternal obesity to placental vascular dysfunction and altered fetal development.
KEYWORDS: maternal obesity, leptin, DNA methylation, placenta, umbilical artery Doppler, fetal programming
References
Institute for Health Metrics and Evaluation (IHME). Global Burden of Disease Results Tool 2021. Seattle: IHME; 2022, article.
Kusuma AANJ, Darmayasa IM, Putra IGM, Suardika A, Pangkahila ES, Duarsa VSP, et al. Hypomethylation of the soluble Fms-like tyrosine kinase 1 (sFlt-1) gene promoter region and elevated sFlt-1 placental expression as risk factors for preeclampsia. Indones Biomed J. 2025; 17(4): 389-96, CrossRef.
Abdualhay RA, Al-Fartosy AJM. Insulin resistance and other adipokines as clinical predictors of gestational diabetes mellitus among pregnant women. Indones Biomed J. 2022; 14(3): 243-51, CrossRef.
Aji AS, Lipoeto NI, Yusrawati Y, Malik SG, Kusmayanti NA, Susanto I, et al. Association between pre-pregnancy body mass index and gestational weight gain on pregnancy outcomes: a cohort study in Indonesian pregnant women. BMC Pregnancy Childbirth. 2022; 22(1): 492, CrossRef.
Kwon EJ, Kim YJ. What is fetal programming? A lifetime health perspective. BMC Pediatr. 2017; 17: 59, CrossRef.
Barker DJP. The fetal and infant origins of adult disease. BMJ. 1995; 311(6998): 171-4, CrossRef.
Catalano PM, Ehrenberg HM. The short- and long-term implications of maternal obesity on the mother and her offspring. BJOG. 2006; 113(10): 1126-33, CrossRef.
Lawlor DA. The developmental origins of health and disease: Where do we go from here? Am J Clin Nutr. 2008; 88(4): 901-6, CrossRef.
Reynolds RM. Glucocorticoid excess and the developmental origins of disease: two decades of testing the hypothesis--2012 Curt Richter Award Winner. Psychoneuroendocrinology. 2013; 38(1): 1-11, CrossRef.
Poston L, Caleyachetty R, Cnattingius S, Corvalán C, Uauy R, Herring S, et al. Influence of maternal obesity on the fetus. Lancet Diabetes Endocrinol. 2016; 4(12): 1025-36, CrossRef.
Louwen F, Kreis NN, Ritter A, Yuan J. Maternal obesity and placental function: Impaired maternal-fetal axis. Arch Gynecol Obstet. 2024; 309(6): 2279-88, CrossRef.
Challier JC, Basu S, Bintein T, Minium J, Hotmire K, Catalano PM, et al. Obesity in pregnancy stimulates macrophage accumulation and inflammation in the placenta. J Clin Endocrinol Metab. 2008; 93(9): 3660-8, CrossRef.
Jansson T, Powell TL. Role of placental nutrient sensing in developmental programming. Clin Obstet Gynecol. 2013; 56(3): 591-601, CrossRef.
Aye ILMH, Powell TL. Jansson T. Review: Adiponectin-the missing link between maternal adiposity, placental transport and fetal growth? Placenta. 2017; 54: 40-5, CrossRef.
Baschat AA. Doppler application in obstetrics. Ultrasound Obstet Gynecol. 2004; 23(5): 471-5, CrossRef.
Alfirevic Z, Stampalija T, Medley N. Fetal and umbilical Doppler ultrasound in high-risk pregnancies. Cochrane Database Syst Rev. 2017; 6(6): CD007529, CrossRef.
Sri CU, Shah S, Shah D, Mitra M, Bijjala S. Effect of maternal body mass index on umbilical artery Doppler changes in pregnancies with fetal growth restriction. Int J Health Sci Res. 2024; 14(8): 162-6, CrossRef.
Avcı ME, Şanlıkan F, Çelik M, Avcı A, Kocaer M, Göçmen A. Effects of maternal obesity on antenatal, perinatal and neonatal outcomes. J Matern Fetal Neonatal Med. 2015; 28(17): 2080-3, CrossRef.
Cody F, Mullers S, Flood K, Unterscheider J, Daly S, Geary M, Kennelly M, et al; Perinatal Ireland Research Consortium. Correlation of maternal body mass index with umbilical artery Doppler in pregnancies complicated by fetal growth restriction and associated outcomes. Int J Gynaecol Obstet. 2021; 154(2): 352-7, CrossRef.
Yusrawati Y, Habibah RL, Machmud R. Differences in maternal leptin serum levels between normal pregnancy and preeclampsia. Indones Biomed J. 2015; 7(1): 37-42, CrossRef.
Anwar AA, Abdullah N, Padjalangi AN, Hamid F, Mappeware NA, Lukas E. Serum leptin concentration is correlated to insulin resistance in polycystic ovary syndrome (PCOS) patients. Mol Cell Biomed Sci. 2021; 5(2): 93-7, CrossRef.
Henson MC, Castracane VD. Leptin in pregnancy: An update. Biol Reprod. 2006; 74(2): 218-29, CrossRef.
Gambino YP, Pérez Pérez A, Dueñas JL, Calvo JC, Sánchez-Margalet V, Varone CL. Regulation of leptin expression by 17beta-estradiol in human placental cells involves membrane associated estrogen receptor alpha. Biochim Biophys Acta. 2012; 1823(4): 900-10, CrossRef.
Pérez-Pérez A, Toro A, Vilariño-García T, Maymó J, Guadix P, Dueñas JL, et al. Leptin action in normal and pathological pregnancies. J Cell Mol Med. 2018; 22: 716-27, CrossRef.
Karakosta P, Roumeliotaki T, Chalkiadaki G, Sarri K, Vassilaki M, Venihaki M, et al. Cord blood leptin levels in relation to child growth trajectories. Metabolism. 2016; 65(6): 874-82, CrossRef.
Mantzoros CS, Rifas-Shiman SL, Williams CJ, Fargnoli JL, Kelesidis T, Gillman MW. Cord blood leptin and adiponectin as predictors of adiposity in children at 3 years of age: A prospective cohort study. Pediatrics. 2009; 123(2): 682-9, CrossRef.
Meyer DM, Brei C, Stecher L, Much D, Brunner S, Hauner H. Leptin in maternal plasma and cord blood as a predictor of offspring adiposity at 5 years: A follow-up study. Obesity. 2018; 26(2): 279-83, CrossRef.
Clapp JF 3rd, Kiess W. Cord blood leptin reflects fetal fat mass. J Soc Gynecol Investig. 1998; 5(6): 300-3, CrossRef.
Moreno-Mendez E, Quintero-Fabian S, Fernandez-Mejia C, Lazo-de-la-Vega-Monroy ML. Early-life programming of adipose tissue. Nutr Res Rev. 2020; 33(2): 244-59, CrossRef.
Smith ZD, Meissner A. DNA methylation: Roles in mammalian development. Nat Rev Genet. 2013; 14(3): 204-20, CrossRef.
Lesseur C, Armstrong DA, Paquette AG, Li Z, Padbury JF, Marsit CJ. Maternal obesity and gestational diabetes are associated with placental leptin DNA methylation. Am J Obstet Gynecol. 2014; 211(6): 654.e1-9, CrossRef.
Daniels TE, Sadovnikoff AI, Ridout KK, Lesseur C, Marsit CJ, Tyrka AR. Associations of maternal diet and placenta leptin methylation. Mol Cell Endocrinol. 2020; 505: 110739, CrossRef.
Chen C, Jiang Y, Yan T, Chen Y, Yang M, Lv M, et al. Placental maternally expressed gene 3 differentially methylated region methylation profile is associated with maternal glucose concentration and newborn birthweight. J Diabetes Investig. 2021; 12(6): 1074-82, CrossRef.
Nogues P, Dos Santos E, Jammes H, Berveiller P, Arnould L, Vialard F, et al. Maternal obesity influences expression and DNA methylation of the adiponectin and leptin systems in human third-trimester placenta. Clin Epigenetics. 2019; 11(1): 20, CrossRef.
Bouchard L, Thibault S, Guay SP, Santure M, Monpetit A, St-Pierre J, et al. Leptin gene epigenetic adaptation to impaired glucose metabolism during pregnancy. Diabetes Care. 2010; 33(11): 2436-41, CrossRef.
Malti N, Merzouk H, Merzouk SA, Loukidi B, Karaouzene N, Malti A, et al. Oxidative stress and maternal obesity: feto-placental unit interaction. Placenta. 2014; 35(6): 411-6, CrossRef.
Choux C, Carmignac V, Bruno C, Sagot P, Vaiman D, Fauque P. The placenta: Phenotypic and epigenetic modifications induced by assisted reproductive technologies throughout pregnancy. Clin Epigenetics. 2015; 7(1): 87. doi: 10.1186/s13148-015-0120-2, CrossRef.
Thakali KM, Faske JB, Ishwar A, Alfaro MP, Cleves MA, Badger TM, et al. Maternal obesity and gestational weight gain are modestly associated with umbilical cord DNA methylation. Placenta. 2017; 57: 194-203, CrossRef.
Mas-Parés B, Xargay-Torrent S, Gómez-Vilarrubla A, Carreras-Badosa G, Prats-Puig A, De Zegher F, et al. Gestational weight Gain relates to DNA methylation in umbilical cord, which, in turn, associates with offspring obesity-related parameters. Nutrients. 2023; 15(14): 3175, CrossRef.
DOI: https://doi.org/10.18585/inabj.v18i1.3911
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