Placental dysfunction in maternal obesity is a key mechanism of fetal programming of metabolic syndrome
https://doi.org/10.18705/2311-4495-2025-12-3-268-282
EDN: OHMKMF
Abstract
The placenta is a critical link between the maternal and fetal bodies and is therefore a central organ to be studied in the context of fetal programming of the metabolic syndrome. Obesity causes placental dysfunction through various mechanisms, including impaired expression of fatty acid transporter genes, esterification en zymes and lipid deposition. The resulting lipotoxic environment, by increasing proinflammatory markers in maternal plasma and placenta, activating placental inflammatory signaling, and upregulating proinflammatory genes, determines intraplacental functional abnormalities and programs long-term metabolic disorders in the fetus. Abnormalities in placental amino acid transport and mitochondrial dysfunction are observed. Evidence of increased placental reactive oxygen species (ROS) levels, protein nitrosylation, altered cytokine concentrations, and increased lipid peroxidation with subsequent endothelial dysfunction of the placental vascular network is recorded. Studies on hormone levels in placental tissues and fetal cord blood in obese women demonstrate various metabolic shifts. Of particular interest is the consideration of sexual dimorphism in the context of fetal programming, showing a cascade of differences in the genetic, metabolic, and inflammatory profile depending on the sex of the fetus. These changes represent mechanisms contributing to placental dysfunction and program ming of obesity and metabolic diseases in the fetus. However, many aspects of placental dysfunction in maternal obesity require further investigation.
About the Authors
M. M. GalagudzaRussian Federation
Mikhail M. Galagudza, MD, Prof., Corresponding Member and Professor of the Russian Academy of Sciences, Director of the Research Institute of Toxicology, Center for Preclinical and Translational Research at the Institute of Experimental Medicine, Head of the Department of Pathology, Almazov National Medical Research Centre; Professor of the Department of Pathophysiology, Academician I. P. Pavlov First Saint Petersburg State University
Parhomenko ave., 15, Saint Petersburg, 194156
Competing Interests:
The authors declare no conflict of interest
Yu. P. Uspensky
Russian Federation
Yuri P. Uspensky, MD, Prof., Head of the Department of Faculty Therapy named after V. A. Waldman, Saint Petersburg State Pediatric Medical University; Professor of the Department of Internal Medicine, Faculty of Stomatology, Academician I. P. Pavlov First Saint Petersburg State University; Chief External Specialist Gastroenterologist of Saint Petersburg
Saint Petersburg
Competing Interests:
The authors declare no conflict of interest
Yu. A. Fominykh
Russian Federation
Yulia A. Fominykh, MD, Prof., Head of the Department of Internal Medicine Propaedeutics with Clinic, Almazov National Medical Research Centre; Professor of the Department of Faculty Therapy named after V. A. Waldman, Saint Petersburg State Pediatric Medical University
Saint Petersburg
Competing Interests:
The authors declare no conflict of interest
D. Yu. Butko
Russian Federation
Dmitry Yu. Butko, MD, Prof., Head of the Department of Medical Rehabilitation and Sports Medicine
Saint Petersburg
Competing Interests:
The authors declare no conflict of interest
V. V. Komar
Russian Federation
Veronika V. Komar, 6th-year student, Faculty of Medicine, Saint Petersburg State Pediatric Medical University, Laboratory Researcher of the Research Institute of Toxicology, Institute of Experimental Medicine, Almazov National Medical Research Centre; Laboratory Assistant of the Department of Faculty Therapy named after V. A. Waldman, Saint Petersburg State Pediatric Medical University
Saint Petersburg
Competing Interests:
The authors declare no conflict of interest
References
1. Babenko AYu, Balukova EV, Baryshnikova NV, et al. / ed. Shabrov AV. Metabolic syndrome. Saint Petersburg, 2020. In Russian ISBN 978-5-907321-19-9.
2. Lima BS, Sanches AP, Ferreira MS, et al. Maternal placental axis and its impact on fetal outcomes, metabolism, and development. Biochim Biophys Acta Mol Basis Dis. 2023;1870(1):16685. DOI:10.1016/j.bbadis.2022.166851.
3. Shook LL, James KE, Roberts DJ, et al. Sex-specific impact of maternal obesity on fetal placental macrophages and cord blood triglycerides. Placenta. 2023;140:100–108. DOI:10.1016/j.placenta.2023.09.006.
4. Kelly AC, Powell TL, Jansson T. Placental function in maternal obesity. Clin. Sci. 2020;134:961–984. DOI:10.1042/CS20190800.
5. Santos E, Hernández M, Sérazin V, et al. Human placental adaptive changes in response to maternal obesity: sex specificities. Int J Mol Sci. 2023;24(11):9770. DOI:10.3390/ijms24119770.
6. Reynolds CM. Don’t sugar coat it: The independent and synergistic impacts of obesity and gestational diabetes on placental parameters. J Physiol. 2023;601(7):1155–1156. DOI:10.1113/JP284347.
7. Padmanabhan V, Cardoso RC, Puttabyatappa M. Developmental programming, a pathway to disease. Endocrinology. 2016;157(4):1328–1340. DOI:10.1210/ en.2015-1934. 8. Şanlı E, Kabaran S. Maternal obesity, maternal overnutrition and fetal programming: effects of epigenetic mechanisms on the development of metabolic disorders. Curr Genomics. 2019;20(6):419–427. DOI:10.2174/13892-02920666191118121651.
8. Lesseur C, Chen J. Adverse maternal metabolic intrauterine environment and placental epigenetics: implications for fetal metabolic programming. Curr Environ Health Rep. 2018;5(4):531–543. DOI:10.1007/s40572-018-0215-6.
9. Chango A, Pogribny IP. Considering maternal dietary modulators for epigenetic regulation and programming of the fetal epigenome. Nutrients. 2015;7:2748–2770. DOI:10.3390/nu7042748.
10. Moreno-Fernandez J, Ochoa JJ, Lopez-Frias M, et al. Impact of early nutrition, physical activity and sleep on the fetal programming of disease in the pregnancy: J. Nutr. 2020;12(12):3900. DOI:10.3390/nu12123900.
11. Zheng J, Xiao X, Zhang Q, et al. DNA methylation: The pivotal interaction between early-life nutrition and glucose metabolism in later life. J. Nutr. 2014;112:1850 1857. DOI:10.1017/S0007114514002827.
12. Marciniak A, Patro-Małysza J, Kimber-Trojnar Ż, et al. Fetal programming of the metabolic syndrome. Taiwan J Obstet Gynecol. 2017 Apr;56(2):133–138. DOI:10.1016/j.tjog.2017.02.002.
13. Fernandez-Twinn DS, Constância M, Ozanne SE. Intergenerational epigenetic inheritance in models of developmental programming of adult disease. Semin. Cell Dev. Biol. 2015;43:85–95. DOI:10.1016/j.semcdb.2015.08.002.
14. Rhee JS, Saben JL, Mayer AL, et al. Diet-induced obesity impairs endometrial stromal cell decidualization: A potential role for impaired autophagy. Hum. Reprod. 2016;31:1315–1326. DOI:10.1093/humrep/dew048.
15. He M, Curran P, Raker C, et al. Placental findings associated with maternal obesity at early pregnancy. Pathol. Res. Pract. 2016;212:282–287. DOI:10.1016/j.prp.2016.01.006.
16. Loardi C, Falchetti M, Prefumo F, et al. Placental morphology in pregnancies associated with pregravid obesity. J Matern Fetal Neonatal Med. 2016; 29(16):2611–6. DOI:10.3109/14767058.2015.1094056.
17. Nogues P, Dos Santos E, Couturier-Tarrade A, et al. Maternal Obesity Influences Placental Nutrient Transport, Inflammatory Status, and Morphology in Human Term Placenta. J Clin Endocrinol Metab. 2021;106(4):e1880-e1896. DOI:10.1210/clinem/dgaa660.
18. Beneventi F, Bellingeri C, De Maggio I, et al. Placental pathologic features in obesity. Placenta. 2023 Dec;144:1–7. DOI:10.1016/j.placenta.2023.10.011.
19. Avagliano L, Monari F, Po’ G, et al. The Burden of Placental Histopathology in Stillbirths Associated With Maternal Obesity. Am J Clin Pathol. 2020;7;154(2):225 235. DOI:10.1093/ajcp/aqaa035.
20. Brouwers L, Franx A, Vogelvang TE, et al. Association of maternal prepregnancy body mass index with placental histopathological characteristics in uncomplicated term pregnancies. Pediatr. Dev. Pathol. 2019;22:45–52. DOI:10.1177/1093526618785838.
21. Wallace JG, Bellissimo CJ, Yeo E, et al. Obesity during pregnancy results in maternal intestinal inflammation, placental hypoxia, and alters fetal glucose metabolism at mid-gestation. Sci Rep. 2019 Nov 26;9(1):17621. DOI:10.1038/s41598-019-54098-x.
22. Brett KE, Ferraro ZM, Yockell-Lelievre J, et al. Maternal-fetal nutrient transport in pregnancy pathologies: the role of the placenta. Int J Mol Sci. 2014;15(9):16153–85. DOI:10.3390/ijms150916153.
23. Howell KR, Powell TL. Effects of maternal obesity on placental function and fetal development. Reproduction. 2017;153(3):R97–R108. DOI:10.1530/REP-16-0615.
24. Dumolt JH, Powell TL, Jansson T. Placental Function and the Development of Fetal Overgrowth and Fetal Growth Restriction. Obstet Gynecol Clin North Am. 2021;48(2):247–266. DOI:10.1016/j.ogc.2021.02.002.
25. Muralimanoharan S, Maloyan A, Myatt L. Mitochondrial function and glucose metabolism in the placenta with gestational diabetes mellitus: role of miR-143. Clin Sci (Lond). 2016 Jun 1;130(11):931–41. DOI:10.1042/CS20160086.
26. Armistead B, Johnson E, VanderKamp R, et al. Placental Regulation of Energy Homeostasis During Human Pregnancy. Endocrinology. 2020;161(7):bqaa076. DOI:10.1210/endocr/bqaa076.
27. Brown K, Heller DS, Zamudio S, et al. Glucose transporter 3 (GLUT3) protein expression in human placenta across gestation. J Placenta. 2011;32:1041–1049. DOI:10.1016/j.placenta.2011.08.006.
28. Acosta O, Ramirez VI, Lager S, et al. Increased glucose and placental GLUT-1 in large infants of obese nondiabetic mothers. Am J Obstet Gynecol. 2015;212(2):227. e1–7. DOI:10.1016/j.ajog.2014.09.006.
29. Kabaran S, Besler HT. Do fatty acids affect fetal programming? J Health Popul Nutr. 2015 Aug 13;33:14. DOI:10.1186/s41043-015-0014-x.
30. Fattuoni C, Mandò C, Palmas F, et al. Preliminary metabolomics analysis of placenta in maternal obesity. Placenta. 2018;61:89–95. DOI:10.1016/j.placenta.2017.11.009.
31. Duttaroy AK, Basak S. Maternal Fatty Acid Metabolism in Pregnancy and Its Consequences in the Feto Placental Development. Front Physiol. 2022;12:787848. DOI:10.3389/fphys.2021.787848.
32. Heerwagen MJR, Gumina DL, Hernandez TL, et al. Placental lipoprotein lipase activity is positively associated with newborn adiposity. Placenta. 2018;64:53 60. DOI:10.1016/j.placenta.2018.03.001.
33. Innis SM. Fatty acids and early human development. Early Hum Dev. 2007;83(12):761–766. DOI:10.1016/j.earlhumdev.2007.09.006.
34. Schaefer-Graf UM, Meitzner K, Ortega Senovilla H, et al. Differences in the implications of том 12 № 3 / 2025 maternal lipids on fetal metabolism and growth between gestational diabetes mellitus and control pregnancies. Diabet. Med. 2011;28:1053–1059. DOI:10.1111/j.1464-5491.2011.03350.x.
35. Segura MT, Demmelmair H, Krauss-Etschmann S, et al. Maternal BMI and gestational diabetes alter placental lipid transporters and fatty acid composition. Placenta. 2017;57:144–51. DOI:10.1016/j.placenta.2017.07.009.
36. Lager S, Ramirez VI, Gaccioli F, et al. Protein expression of fatty acid transporter 2 is polarized to the trophoblast basal plasma membrane and increased in placentas from overweight/obese women. Placenta. 2016;40:60–66. DOI:10.1016/j.placenta.2016.03.003.
37. Calabuig-Navarro V, Haghiac M, Minium J, et al. Effect of maternal obesity on placental lipid metabolism. Endocrinology. 2017;158:2543–2555. en.2017-00155. DOI:10.1210/
38. Moore GS, Allshouse AA, Fisher BM, et al. Can Fetal Limb Soft Tissue Measurements in the Third Trimester Predict Neonatal Adiposity? J Ultrasound Med. 2016;35:1915–1924. DOI:10.7863/ultra.15.08058.
39. Saben J, Lindsey F, Zhong Y, et al. Maternal obesity is associated with a lipotoxic placental environment. Placenta. 2014;35(3):171–7. DOI:10.1016/j.placenta.2013.12.001.
40. Rasool A, Mahmoud T, Mathyk B, et al. Obesity downregulates lipid metabolism genes in first trimester placenta. Sci Rep. 2022;12(1):19368. DOI:10.1038/s41598 022-23847-x.
41. Prieto-Sanchez MT, Ruiz-Palacios M, Blanco Carnero JE, et al. Placental MFSD2a transporter is related to decreased DHA in cord blood of women with treated gestational diabetes. Clin. Nutr. 2017;36:513–521. DOI:10.1016/j.clnu.2016.03.007.
42. Sanchez-Campillo M, Ruiz-Palacios M, Ruiz Alcaraz AJ, et al. Child head circumference and placental MFSD2a expression are associated to the level of MFSD2a in maternal blood during pregnancy. Front. Endocrinol. (Lausanne). 2020;11:38. DOI:10.3389/fendo.2020.00038.
43. Gallo LA, Barrett HL, Dekker M. Placental transport and metabolism of energy substrates in maternal obesity and diabetes. Nitert. 2017;54:59–67. DOI:10.1016/j. placenta.2016.12.006.
44. Desforges M, Mynett KJ, Jones RL, et al. The SNAT4 isoform of the system A amino acid transporter is functional in human placental microvillous plasma membrane. J. Physiol. 2009;587:61–72. DOI:10.1113/jphysiol.2008.163353.
45. Cleal JK, Glazier JD, Ntani G, et al. Facilitated transporters mediate net efflux of amino acids to the fetus across the basal membrane of the placental syncytiotrophoblast. J. Physiol. DOI:10.1113/jphysiol.2010.198946. 2011;589:987–997.
46. Jones HN, Woollett LA, Barbour N, et al. High fat diet before and during pregnancy causes marked up-regulation of placental nutrient transport and fetal overgrowth in C57/BL6 mice, J. FASEB. 2009;23(1):271–8. DOI:10.1096/fj.08-112343.
47. Jansson N, Rosario FJ, Gaccioli F, et al. Activation of placental mTOR signaling and amino acid transporters in obese women giving birth to large babies. The Journal of Clinical Endocrinology & Metabolism. 2012;98(1):105 113. DOI:10.1210/jc.2012-2594.
48. Díaz P, Powell TL, Jansson T. The role of placental nutrient sensing in maternal-fetal resource allocation. Biol Reprod. 2014;91(4):82. DOI:10.1095/ biolreprod.114.122847.
49. Saben J, Lindsey F, Zhong Y, et al. Maternal obesity is associated with a lipotoxic placental environment. Placenta. 2014 Mar;35(3):171–7. DOI:10.1016/j.placenta.2013.12.001.
50. Saben J, Zhong Y, Gomez-Acevedo H, et al. Early growth response protein-1 mediates lipotoxicity associated placental inflammation: role in maternal obesity. Am J Physiol Endocrinol Metab. 2013;305(1):E1–14. DOI:10.1152/ajpendo.00085.2013.
51. Challier JC, Basu S, Bintein T, et al. Obesity in pregnancy stimulates macrophage accumulation and inflammation in the placent. Placenta. 2008;29(3):274–81. DOI:10.1016/j.placenta.2007.12.007.
52. Brombach C, Tong W, Giussani DA. Maternal obesity: new placental paradigms unfolded. Trends Mol Med. 2022;28(10):823–835. DOI:10.1016/j.molmed.2022.08.001.
53. Aye ILMH, Lager S, Ramirez VI, et al. Increasing maternal body mass index is associated with systemic inflammation in the mother and the activation of distinct placental inflammatory pathways. Biol Reprod. 2014;90(6):129. DOI:10.1095/biolreprod.114.118944.
54. Simon B, Bucher M, Maloyan A. A primary human trophoblast model to study the effect of inflammation associ ated with maternal obesity on regulation of autophagy in the placenta. J Vis Exp. 2017;127:56–84. DOI:10.3791/56484.
55. Linnemann K, Malek A, Sager R, et al. Leptin production and release in the dually in vitro perfused human placenta. J Clin Endocrinol Metab. 2000;85:4298–4301. DOI:10.1210/jcem.85.11.7013.
56. Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature. 2011;469(7330):323 335. DOI:10.1038/nature09783.
57. Yang C-S, et al. Autophagy protein rubicon mediates phagocytic NADPH oxidase activation in response to microbial infection or TLR stimulation. Cell Host & Microbe. 2012;11(3):264–276. DOI:10.1016/j.chom.2012.01.018.
58. Zi Z, et al. Rubicon deficiency enhances cardiac autophagy and protects mice from lipopolysaccharide induced lethality and reduction in stroke volume. J. Cardiovasc. Pharmacol. 2015;65(3):252–261. DOI:10.1097/ FJC.0000000000000188.
59. Perrone S, Santacroce A, Picardi A, et al. Fetal programming and early identification of newborns at high risk of free radical-mediated diseases. World J Clin Pediatr. 2016;5(2):172–81. DOI:10.5409/wjcp.v5.i2.172.
60. Santos-Rosendo C, Bugatto F, González Domínguez A, et al. Placental adaptive changes to protect function and decrease oxidative damage in metabolically healthy maternal obesity. Antioxidants (Basel). 2020;9(9):794. DOI:10.3390/antiox9090794.
61. Pereira RD, De Long NE, Wang RC, et al. Angiogenesis in the placenta: the role of reactive oxygen species signaling. Biomed Res Int. 2015;2015:814543. DOI:10.1155/2015/814543.
62. Hu C, Yang Y, Li J, et al. Maternal diet induced obesity compromises oxidative stress status and angiogenesis in the porcine placenta by upregulating Nox2 expression. Oxid Med Cell Longev. 2019:2019:2481592. DOI:10.1155/2019/2481592.
63. Hu C, Yan Y, Ji F, et al. Maternal obesity increases oxidative stress in placenta and it is associated with intestinal microbiota. Front Cell Infect Microbiol. 2021;11:671347. DOI:10.3389/fcimb.2021.671347.
64. Parrettini S, Caroli A, Torlone E. Nutrition and metabolic adaptations in physiological and complicated pregnancy: focus on obesity and gestational diabetes. Front Endocrinol (Lausanne). 2020;11:611929. DOI:10.3389/fendo.2020.611929.
65. Musial B, Vaughan OR, Fernandez-Twinn DS, et al. A Western-style obesogenic diet alters maternal metabolic phys iology with consequences for fetal nutrient acquisition in mice. J Physiol. 2017;595:4875–4892. DOI:10.1113/JP274100.
66. Musa E, Salazar-Petres E, Arowolo A, et al. Obesity and gestational diabetes independently and collectively induce specific effects on placental structure, inflammation and endocrine function in a cohort of South African women. J Physiol. 2023;601(7):1287–1306. DOI:10.1113/JP284346.
67. Hufnagel A, Dearden L, Fernandez-Twinn DS, et al. Programming of cardiometabolic health: the role of maternal and fetal hyperinsulinaemia. J Endocrinol. 2022;253(2):R47–R63. DOI:10.1530/JOE-21-0268.
68. Lynch TA, Westen E, Li D, et al. Stillbirth in women with diabetes: a retrospective analysis of fetal autopsy reports. Journal of Maternal-Fetal and Neonatal Medicine. 2020;Jun;35(11):2091–2098. DOI:10.1080/1476-7058.2020.1779213.
69. Aye ILMH, Rosario FJ, Powell TL, et al. Adiponectin supplementation in pregnant mice prevents the adverse effects of maternal obesity on placental function and fetal growth. Proc Natl Acad Sci U S A. 2015;112(41):12858 63. DOI:10.1073/pnas.1511222112.
70. Qiao L, Wattez JS, Lee S, et al. Adiponectin Deficiency Impairs Maternal Metabolic Adaptation to Pregnancy in Mice. Diabetes. 2017;66(5):1126–1135. DOI:10.2337/db16-1127.
71. Lis-Kuberka J, Pupek M, Orczyk-Pawiłowicz M. The Mother-Child Dyad Adipokine Pattern: A Review of Current Knowledge. Nutrients. 2023;15(18):4059. DOI:10.3390/nu15184059.
72. Matjila M, Millar R, Van Der Spuy Z, et al. Elevated placental expression at the maternal-fetal interface but diminished maternal circulatory kisspeptin in preeclamptic pregnancies. Pregnancy Hypertens. 2016;6(1):79–87. DOI:10.1016/j.preghy.2015.11.002.
73. Sferruzzi-Perri AN, Lopez-Tello J, Napso T, et al. Exploring the causes and consequences of maternal metabolic maladaptations during pregnancy. Placenta. 2020;98:43–51. DOI:10.1016/j.placenta.2020.06.012.
74. Muralimanoharan S, Guo C, Myatt L, et al. Sexual dimorphism in miR-210 expression and mitochondrial dysfunction in the placenta with maternal obesity. Int J Obes (Lond). 2015;39(8):1274–81. DOI:10.1038/ijo.2015.53.
75. Thum T, Galuppo P, Wolf C, et al. J. MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure. Circulation. 2007;116(3):258–67. DOI:10.1161/ CIRCULATIONAHA.107.687941.
76. Beetch M, Alejandro EU. Placental mTOR Signaling and Sexual Dimorphism in Metabolic Health across the Lifespan of Offspring. Children (Basel). 2021;8(11):970. DOI:10.3390/children8110970.
77. Bale TL. The placenta and neurodevelopment: sex differences in prenatal vulnerability. dialogues clin. Neurosci. 2016;18:459–464. DOI:10.31887/DCNS.2016.18.4/tbale.
78. Muralimanoharan S, Gao X, Weintraub S, et al. Sexual dimorphism in activation of placental autophagy in obese women with evidence for fetal programming from a placenta-specific mouse model. Autophagy. 2016;12(5):752 69. DOI:10.1080/15548627.2016.1159330.
79. Tarrade A, Panchenko P, Junien C, et al. Placental contribution to nutritional programming of health and diseases: epigenetics and sexual dimorphism. J Exp Biol. 2015;218(Pt 1):50–8. DOI:10.1242/jeb.107475.
80. Powell TL, Uhlson C, Madi L, et al. Fetal sex differences in placental LCPUFA ether and plasmalogen phosphatidylethanolamine and phosphatidylcholine contents in pregnancies complicated by obesity. Biol Sex Differ. 2023;14(1):66. DOI:10.1186/s13293-023-00543-1.
81. Powell TL, Barner K, Madi L, et al. Sex-Specific Responses in Placental Fatty Acid Oxidation, Esterification and Transfer Capacity to Maternal Obesity. Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2021;1866:158861. DOI:10.1016/j.bbalip.2021.158861.
82. Kim DW, Young SL, Grattan DR, et al. Obesity during pregnancy disrupts placental morphology, cell proliferation, and inflammation in a sex-specific manner across gestation in the mouse. Biol Reprod. 2014;90(6):130. DOI:10.1095/biolreprod.114.118945.
83. Tozour J, Hughes F, Carrier A, et al. Prenatal hyperglycemia exposure and cellular stress, a sugar coated view of early programming of metabolic diseases. Biomolecules. 2020;10(10):1359. DOI:10.3390/biom10101359.
Review
For citations:
Galagudza M.M., Uspensky Yu.P., Fominykh Yu.A., Butko D.Yu., Komar V.V. Placental dysfunction in maternal obesity is a key mechanism of fetal programming of metabolic syndrome. Translational Medicine. 2025;12(3):268-282. (In Russ.) https://doi.org/10.18705/2311-4495-2025-12-3-268-282. EDN: OHMKMF