Дисфункция плаценты при материнском ожирении — ключевой механизм фетального программирования метаболического синдрома у плода

Плацента является важнейшим связующим звеном между организмом матери и плода и, следователь но, центральным органом, подлежащим изучению в контексте фетального программирования метаболи ческого синдрома. Ожирение вызывает дисфункцию плаценты за счет различных механизмов, включая нарушение экспрессии генов-переносчиков жирных кислот, ферментов этерификации и депонирования липидов. Формирующаяся при этом липотоксичная среда за счет повышения уровня ряда провоспали тельных маркеров как в материнской плазме, так и в плаценте, активации плацентарной передачи сигна лов воспаления, а также усиления регуляции провоспалительных генов, определяет внутриплацентар ные функциональные нарушения и программирует долгосрочные метаболические нарушения у плода. Наблюдаются нарушения в плацентарном транспорте аминокислот, а также митохондриальная дисфунк ция. Регистрируются данные о повышении уровня плацентарных активных форм кислорода (АФК), ни трозилировании белков, изменении концентрации цитокинов, усилении перекисного окисления липидов с последующей эндотелиальной дисфункцией плацентарной сосудистой сети. Результаты исследований по определению уровня гормонов как в тканях плаценты, так и в пуповинной крови плода у женщин с ожирением демонстрируют различные метаболические сдвиги. Особый интерес представляет рас смотрение полового диморфизма в контексте фетального программирования. Показано, что существует определенный каскад различий генетического, метаболического, воспалительного профиля в зависимости от пола плода. Эти изменения представляют собой механизмы, способствующие плацентарной дисфункции и программированию у плода ожирения и метаболических заболеваний, которые реализуются в более позднем возрасте. При этом многие аспекты дисфункции плаценты при ожирении у матери требуют дальнейшего изучения.

1. Бабенко А.Ю., Балукова Е.В., Барыш никова Н.В. и др. / Под ред. А. В. Шаброва Метаболический синдром. Санкт-Петербург, 2020. 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.