Abstract
The prevalence of maternal obesity rapidly increases, which represents a major public health concern worldwide. Maternal obesity is characteristic by metabolic dysfunction and chronic inflammation. It is associated with health problems in both mother and offspring. Increasing evidence indicates that the placenta is an axis connecting maternal obesity with poor outcomes in the offspring. In this brief review, we have summarized the current data regarding deregulated placental function in maternal obesity. The data show that maternal obesity induces numerous placental defects, including lipid and glucose metabolism, stress response, inflammation, immune regulation and epigenetics. These placental defects affect each other and result in a stressful intrauterine environment, which transduces and mediates the adverse effects of maternal obesity to the fetus. Further investigations are required to explore the exact molecular alterations in the placenta in maternal obesity, which may pave the way to develop specific interventions for preventing epigenetic and metabolic programming in the fetus.
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Introduction
Obesity, commonly defined by body mass index (BMI), is a growing public health concern and its prevalence is steadily increasing worldwide [1, 2]. It is estimated that 2.7 billion adults will be overweight (BMI 25.0–29.9 kg/m2), over one billion will be obese (obesity class I and II, BMI 30.0–39.9 kg/m2), and 177 million will be extremely obese by 2025 (obesity class III, BMI ≥ 40.0 kg/m2) [3, 4]. While 29.0% of women giving birth had obesity in the United States in 2019 [5], 45.7% of women were overweight or obese in Europe in 2019 [6]. Maternal obesity, characteristic by metabolic dysfunction and chronic inflammation, negatively affects placental function and fetal development [7, 8], resulting in epigenetic and metabolic changes in the offspring [9]. From mother’s perspective, maternal obesity is associated with multiple pregnancy complications, such as spontaneous abortion, Caesarean delivery, and increased risk of developing gestational diabetes mellitus (GDM) and preeclampsia (PE) [10, 11]. Moreover, mothers with obesity are highly associated with hypertension, diabetes, and depression in later life [12]. From infant’s perspective, maternal obesity is linked to small for gestational age (SGA) infants, even more frequently, large for gestational age (LGA) newborns [10, 12], and stillbirth, particularly in males [13]. Importantly, children born to women with obesity are at an increased risk of obesity, metabolic disease, neuropsychiatric and cognitive disorders, and deregulated immunity [14,15,16]. The association between maternal obesity and health problems in the offspring suggests a transmission of metabolic disease from the mother to the child.
Maternal obesity
Obesity is caused by an imbalance between food intake and energy expenditure [17]. Obesity affects many systems and organs, such as the adipose tissue, which is an important metabolic and endocrine organ. Adipose tissue produces and releases various bioactive factors, including nutrients, hormones, adipokines, growth factors, enzymes, and extracellular vesicles that modulate energy balance, glucose and lipid homeostasis, tissue repair, inflammatory regulation, and immune response [18,19,20,21]. Obesity alters the structure, composition, regulation, and function of adipose tissue, along with many changes in other organs. Maternal obesity is thus associated with deregulated circulating factors, particularly metabolites like glucose and lipids, adipokines including leptin and adiponectin, growth factors for example insulin-like-growth factors (IGFs), and inflammatory cytokines such as interleukin 6 (IL6), IL8, tumor necrosis factor α (TNFα), monocyte chemoattractant protein 1 (MCP-1), and C-reactive protein (CRP) [7, 19, 20]. In particular, elevated lipids, leptin and IL6 are inflammatory mediators, which play important roles in the development of maternal obesity and metabolic dysfunction. While many metabolites in the maternal circulation, such as glucose and lipids, are likely transmitted across the placental barrier, causing fetal hyperglycemia and hyperlipidemia and negatively affecting fetal development [7], an array of maternal metabolic and inflammatory signals directly regulate placental function [22, 23]. Maternal metabolites, hormones, growth factors, and cytokines that are altered in maternal obesity result in an “obesorgenic” metabolic environment, which leads to changes in placental function, fetal growth and development. Although the molecular mechanisms remain elusive, emerging evidence indicates that an impaired placenta, the maternal–fetal axis, mediates this metabolic environment from mothers with obesity to adverse short- and long-term outcomes in the offspring.
The placenta
The placenta, a temporary organ, is the interface between the mother and the fetus. It is essential for fetal growth and development and a key for a successful pregnancy [24]. The human placenta is composed of a fetal part or chorionic plate and a maternal part or basal plate. The chorionic plate is covered by the amnion, which is composed of a single layer of stratified epithelium and amniotic mesenchyme, an avascular connective tissue [25]. The placenta provides nutrients and oxygen to the growing fetus, produces and releases bioactive factors, such as hormones, growth factors, cytokines, and microRNAs/long non-coding RNAs/circular RNAs (miRNAs/lncRNAs/cirRNAs), and removes waste products [24, 26]. Moreover, the placenta serves as a defense front against pathogens through multiple mechanisms, including triggering interferon type III signaling, miRNA-mediated autophagy and the nuclear factor-κB (NF-κB) pathway [26, 27]. The placenta contains various placental cells including trophoblasts, immune cells, stromal cells and endothelial cells. Its development depends on the differentiation of progenitor cells, termed villous cytotrophoblasts (vCTBs), into the syncytiotrophoblast (STB) as well as extravillous trophoblasts (EVTs) [28]. While the STB builds the important interface between maternal and fetal blood [29], vCTBs of the anchoring villi differentiate into invasive interstitial EVTs, which invade the maternal decidua and remodel the uterine spiral arteries [30]. A variety of molecular signaling pathways, such as Notch and Wnt (wingless/integrated), regulates placental development and controls trophoblast stemness, differentiation, and function [31].
Interestingly, a large body of epidemiological data suggests that altered placental function increases the risk of obesity, metabolic and cardiovascular diseases in the adult life of the offspring [32,33,34]. In further support, studies in mice demonstrate that the placenta directly impacts fetal brain development and that changed placental function mediates maternal complications to adverse fetal neurodevelopment [35,36,37,38]. These observations highlight that the placenta is the key, determining life-long metabolic and mental health and connecting maternal obesity with poor outcomes in the offspring.
Changed placenta in maternal obesity
Altered bioactive factors in maternal obesity may directly regulate intracellular signaling pathways in trophoblastic cells of the placenta. In line with this notion, the STB, the transporting epithelium in the placenta, expresses receptors for glucose transporters (GLUTs), insulin, leptin, and IGF-1 in its maternal-facing microvillous plasma membrane [39,40,41]. Through these signaling pathways, maternal obesity associated alterations can thus negatively affect the placenta in diverse aspects, such as placental metabolism, mitochondrial function, inflammation modulation, oxidative response and epigenetics. Pathologically, the rate of maternal placental vascular lesions was higher in women with obesity than in women with normal weight [42]. Maternal obesity was significantly associated with both maternal- and fetal overall vascular malperfusion, inflammatory lesions, and villitis [43]. As placenta is a fetal tissue, it exhibits sexual dimorphism. Indeed, fetal sex affected significantly the effect of maternal obesity on placental inflammatory lesions showing an increased incidence rate of chronic villitis and fetal thrombosis in female placentas [44]. Studies have further revealed distinct sexually dimorphic profiles of gene expression in the placenta, particularly, genes responsible for immune response and inflammatory regulation [45,46,47,48,49]. Early developmental stresses in the placenta are believed to be transduced into the offspring through fetal epigenetic and metabolic reprogramming [9, 50, 51].
Deregulated metabolism in the placenta
The placenta maintains high metabolic activity to fulfill its roles in providing the fetus with nutrients, hormones and oxygen during pregnancy [52]. While circulating lipids are elevated during pregnancy in all women, maternal obesity is associated with an altered maternal lipid profile: compared with control pregnant women, pregnant women with obesity displayed lower high-density lipoprotein (HDL) levels in the first trimester and higher maternal triglyceride (TG) levels in the second and third trimester [53]. In addition, non-esterified (free) fatty acids (NEFA), hydrolyzed products of TGs, were also elevated in maternal plasma throughout gestation in women with obesity [53].
Altered metabolism in maternal obesity leads to metabolic deregulation in the placenta. Placental omics studies demonstrate that lipid metabolism was altered in the placenta from women with obesity [54,55,56]. These placentas displayed increased lipoprotein lipase activity [57]. The expression of genes responsible for lipid transport mechanisms was also deregulated, such as genes encoding fatty acid transport protein 2 (FATP2) and FATP4 [58, 59]. This leads to changed placental lipid profile in maternal obesity. In fact, placentas from women with obesity displayed elevated levels of TGs, free fatty acids (FFAs), NEFAs, and cholesterol [8]. The transcriptomic analysis of term placentas from women with obesity further revealed differential expression of genes associated with lipid metabolism, such as decreased DKK1 (Dickkopf homolog 1) [60] and ANGPTL4 (angiopoietin-like 4) [61]. In further support, the results from placental proteomic analysis were consistent with increased lipid synthesis and altered antioxidant capacity in placentas from women with obesity [62]. These alterations facilitate placental lipid accumulation, reduce lipid transport to the developing fetus, and induce a lipotoxic placental environment that associates with cellular stress and inflammation. The data strengthen the notion that maternal obesity is associated with placental lipotoxicity [63, 64].
Glucose is the primary substrate for placental and fetal energy metabolism. To promote placental and fetal glucose delivery, pregnancy is accompanied by alterations in maternal glucose metabolism, including insulin resistance, activation of hepatic glucose production and increased β-cell insulin release with higher plasma C-peptide [65]. Women with obesity had 50–60% higher postprandial insulin concentrations than control women in both early and late gestation [66]. Women with obesity were more glucose intolerant than pregnant women with normal weight, as evidenced by higher fasting, 1-h and 2-h glucose levels following an oral glucose tolerance test [66]. Glucose transfer to the fetus occurs via a concentration gradient, which is mainly mediated by the GLUT family. The expression of different isoforms of the GLUT transporter was altered by an obesogenic maternal environment and these alterations mirrored the trends in fetal growth and birth weight at term [67, 68]. These findings underscore the notion that deregulated metabolism of maternal obesity leads to deregulated placental metabolism.
Altered immune cells in the placenta
Maternal immunity plays a critical role in pregnancy and the development of healthy offspring. Maternal immune cells, including uterine macrophages, natural killer cells, dendritic cells and mast cells, are present in the placenta [69]. While maintaining host defense against pathogens [26], maternal immune cells initiate and support implantation, placentation, and parturition [70]. Maternal obesity enhanced the number of maternal macrophages and innate immune cells associated with accumulated macrophages in the placental villous stroma, promoting inflammation, oxidative stress, mitochondrial dysfunction and metabolic deregulation [71, 72]. In addition, an increased ratio of pro-inflammatory M1 macrophages versus anti-inflammatory M2 macrophages was reported [73]. These macrophages produced pro-inflammatory cytokines, including IL6, TNFα and MCP-1 [71, 74, 75], enforcing placental inflammation. Moreover, the placenta normally helps to skew the maternal and fetal environment toward a CD4+ helper T cell type-2 (Th2) and anti-inflammatory profile, whereas obesity and other stress factors create a more CD4 + helper T cell type-1 (Th1) and inflammatory gestational environment [76]. Furthermore, maternal obesity and obesogenic diets have been associated with abnormal immune function in the offspring, including decreased response to infection, atopic disease, and asthma [77,78,79].
Inflammatory placenta
Obesity is associated with enhanced inflammation, referred to as “metaflammation” for the chronic, low-grade inflammatory state [80]. Metaflammation is triggered by metabolites and nutrients that lead to systemic insulin resistance [80, 81]. This metaflammation in pregnant women with obesity initiates a cascade of events, leading to an inflammatory utero environment.
Indeed, maternal cytokines and adipokines link maternal metaflammation to placental function. Similar to maternal plasma, the placenta also showed increased levels of inflammatory markers, such as IL6, IL8, IL1β, and MCP-1 [81, 82]. Multiple factors, including lipids [83], oxidized lipids [84], reactive oxygen species (ROS) [85], and endotoxin [86], stimulate placental inflammation. This cytokine profile is driven by multiple inflammatory pathways, including the activation of receptors for advanced glycation end products (RAGEs) [87] and activation of Toll-like receptor 4 (TLR4) [88]. In turn, these pathways promote NF-κB, c-Jun N-terminal kinase (JNK), and rat sarcoma virus (Ras) signaling, resulting in an increased generation of ROS and secretion of the inflammatory cytokines [89]. Placental inflammation impairs overall placental function. Particularly, early inflammation has been reported to affect the developing immunophenotypes of fetal immune cells, which is likely related to the effects of obesity on epigenetics and the microbiome [77, 90, 91].
Stressed placenta
Pregnancy is linked to heightened oxidative stress, partially due to the high metabolic demand of the placenta [90]. Mitochondria are the major source of ROS under normal physiological conditions. ROS are vital signaling molecules of redox-sensitive pathways, including autophagy, cell differentiation, and inflammatory response [92]. ROS triggered the expression of vascular endothelial growth factor (VEGF) and GLUTs to promote angiogenesis in early pregnancy [93]. In contrast, excess ROS generated by mitochondria and/or decreased total antioxidant capacity (TAC) were shown to disrupt cellular and tissue homeostasis by promoting oxidative stress, damaging proteins, lipids, and nucleic acids [8]. Maternal obesity was associated with increased maternal ROS, including higher levels of maternal nitric oxide and superoxide anions [94, 95]. Moreover, ROS production [72], glutathione concentrations and superoxide dismutase (SOD) activity [95] in the placenta were reported to be increased in maternal obesity, which may impair mitochondrial function and reduce ATP production [72]. In further support, the proteomic signature showed altered antioxidant capacity in placentas from women with obesity [62]. Reduced placental mTOR gene expression and up-regulation of genes involved in oxidative stress and mitochondrial function, such as increased sirtuin 1 (SIRT1) and uncoupling protein 2 (UCP2), were reported in maternal obesity [96]. It was also revealed that highly increased ROS led to mitochondrial dysfunction, placental inflammation and fetal epigenetic changes [97, 98].
Inflammation and metabolic dysfunction also increase placental endoplasmic reticulum (ER) stress and downstream activation of the placental unfolded protein response (UPR), which has been extensively reviewed [8]. Along with deregulated metabolism, inflammation, immune deregulation, these cellular stresses impair placental function and fetal development, which may cause long-term alterations in the immune and nervous system of the offspring [70].
Placental epigenetic changes
Altered placental epigenetics, including DNA methylation, may mediate adverse outcomes in the offspring [50]. Compared to a plenty of placental epigenetic investigations in pregnancy complicated by diabetes, only a smaller proportion of studies focused on epigenetic alterations in pregnancy complicated by obesity alone [50]. Nevertheless, differentially-methylated genes, such as ADIPOQ (adiponectin), ADIPOR1 (adiponectin receptor 1), LEP (leptin) and LEPR (leptin receptor), were reported in placental tissue in maternal obesity [99, 100]. Recently, it has been revealed that placental DNA methylation alterations were associated with maternal pre-pregnancy BMI and gestational weight gain [101]. Maternal obesity is further reported to be linked to increased DNA methylation and decreased RNA methylation in the human term placenta [102]. Interestingly, based on the data derived from ten studies with 2631 mother-child pairs from the Pregnancy and Childhood Epigenetics (PACE) consortium, 27 CpG sites were identified to be differentially methylated in placental tissue DNA from women with obesity [103]. Moreover, 104 CpG sites annotating for 97 genes in the placenta were reported to be differentially methylated with gestational weight gain [104]. Particularly, CpG sites annotating for FRAT1 (frequently rearranged in advanced T cell lymphomas-1), SNX5 (sorting nexin 5) and KCNK3 (potassium channel subfamily K member 3) genes were correlated with an adverse metabolic phenotype in the offspring [104]. In sum, these data demonstrate that maternal obesity is associated with epigenetic changes in the placenta. More studies are needed to further explore the impact of maternal obesity on epigenetic alterations in placental tissue as well as in various placental cell populations at different gestational stages.
Cord blood cell epigenetic alterations
Placental dysfunctions associated with maternal obesity affect each other, resulting in a stressful intrauterine environment, which associates with poor outcomes, especially, with programing the fetus for disease in later life [47, 105, 106]. Indeed, maternal pre-pregnancy BMI was linked to decreased methylation at five CpG sites near the LEP transcription start suggesting an association between maternal and fetal obesity [107]. Methylation of serotonin regulating genes in cord blood cells was correlated with maternal metabolic parameters [108]. Moreover, gestational weight gain in pregnant women with obesity was associated with cord blood cell DNA methylation [109]. Average methylated cytosine levels in both the CpG islands and promoters were shown to be significantly decreased in cord blood from overweight and obese groups [110]. Importantly, a longitudinal birth cohort study, which was across a period from birth to 18 years, showed a significant connection between cord DNA methylation marks and postnatal BMI trajectories [111]. These data show that fetal epigenetic alteration is a potential underlying mechanism for poor outcomes of the offspring.
Potential clinical intervention
Restoration of placental function will reduce the adverse outcomes caused by maternal obesity. Prior and during pregnancy are time windows to prevent the negative consequences of poor in utero environments and to improve the long-term outcomes of the mother and the child. It is necessary for women of reproductive age to receive education about maternal and fetal risks associated with maternal obesity. Exercise and lifestyle modifications may positively affect maternal and fetal outcomes. In fact, exercise and healthy diets during pregnancy were shown to be able to influence the offspring’s lean mass and early growth [112]. Further potential interventions, including supplementation of omega 3 polyunsaturated fatty acids (n-3 LCPUFAs), DHA (docosahexaenoic acid), melatonin, or anti-inflammatory agents, have been discussed [7]. Activation of the adiponectin receptor in the placenta has also been proposed to be a promising strategy [7]. This is supported by the data from animal experiments showing that normalization of maternal adiponectin in obese pregnant mice prevented cardiac dysfunction and improved glucose metabolism in the adult offspring [113, 114]. Moreover, studies have underlined the importance of the gut microbiome in the transmission of the obesity phenotype and dietary interventions are thus considered as potential strategy to improve maternal and fetal outcomes [115,116,117]. Especially, novel anti-inflammatory diets during pregnancy should be explored to prevent metabolic dysfunction in the offspring [118]. In addition, vitamin D deficiency has been reported to be partially responsible for placental mitochondrial dysfunction and increased inflammation, and its supplementation is thus proposed to be beneficial in improving placental function [119]. Collectively, although much has been done, it is still a long way to go to discover targeted and effective strategies to prevent and reduce adverse maternal and fetal outcomes induced by maternal obesity.
Conclusion
The prevalence of maternal obesity is rapidly increasing and the poor short- and long-term outcomes in both mothers and infants represent a major public health problem worldwide. In this brief review, we have summarized the data showing that maternal obesity associated with deregulated metabolism and metaflammation greatly impairs placental development and function, as evidenced by placental defects in lipid and glucose metabolism, stress response, inflammation, immune regulation and epigenetics (Fig. 1). These defects affect each other and result in a stressful intrauterine environment, which transduces and mediates the adverse effects of maternal obesity to the fetus, leading to poor outcomes in the offspring (Fig. 1).
The placenta holds the key to better understand the molecular pathophysiology linking maternal obesity to poor outcomes. Further investigations are required to explore molecular alterations in the placenta in response to maternal obesity. In particular, advanced sequencing approaches [120, 121] represent powerful tools to further study placental ‘omics’ in maternal obesity. The establishment of human trophoblast stem cells [122] and placental organoids [123, 124] also provides novel tools for investigating the impact of maternal obesity on placental function. In addition to trophoblasts, placental mesenchymal stromal/stem cells [125] may also play important roles in mediating the effect of maternal obesity on the placenta. Studies employing these novel techniques may pave the way for developing specific interventions to prevent epigenetic and metabolic programming in the offspring.
Data availability
Not applicable.
References
Inoue Y, Qin B, Poti J, Sokol R, Gordon-Larsen P (2018) Epidemiology of obesity in adults: latest trends. Curr Obes Rep 7(4):276–288
Chooi YC, Ding C, Magkos F (2019) The epidemiology of obesity. Metabolism 92:6–10
Pati S, Irfan W, Jameel A, Ahmed S, Shahid RK (2023) Obesity and cancer: a current overview of epidemiology, pathogenesis, outcomes, and management. Cancers 15(2):485
Kelly T, Yang W, Chen CS, Reynolds K, He J (2008) Global burden of obesity in 2005 and projections to 2030. Int J Obes 32(9):1431–1437
Driscoll AK, Gregory ECW (2021) Prepregnancy body mass index and infant outcomes by race and Hispanic origin: United States, 2020. Natl Vital Stat Rep 70(16):1–8
Commission E (2019) Overweight and obesity—BMI statistics. Open Research Europe
Kelly AC, Powell TL, Jansson T (2020) Placental function in maternal obesity. Clin Sci 134(8):961–984
Brombach C, Tong W, Giussani DA (2022) Maternal obesity: new placental paradigms unfolded. Trends Mol Med 28(10):823–835
Tomar AS, Tallapragada DS, Nongmaithem SS, Shrestha S, Yajnik CS, Chandak GR (2015) Intrauterine programming of diabetes and adiposity. Curr Obes Rep 4(4):418–428
Stubert J, Reister F, Hartmann S, Janni W (2018) The risks associated with obesity in pregnancy. Dtsch Arztebl Int 115(16):276–283
Sebire NJ, Jolly M, Harris JP, Wadsworth J, Joffe M, Beard RW, Regan L, Robinson S (2001) Maternal obesity and pregnancy outcome: a study of 287,213 pregnancies in London. Int J Obes Relat Metab Disord 25(8):1175–1182
Stang J, Huffman LG (2016) Position of the academy of nutrition and dietetics: obesity, reproduction, and pregnancy outcomes. J Acad Nutr Diet 116(4):677–691
Aune D, Saugstad OD, Henriksen T, Tonstad S (2014) Maternal body mass index and the risk of fetal death, stillbirth, and infant death: a systematic review and meta-analysis. JAMA 311(15):1536–1546
Howell KR, Powell TL (2017) Effects of maternal obesity on placental function and fetal development. Reproduction 153(3):R97–R108
Zhang C, Hediger ML, Albert PS, Grewal J, Sciscione A, Grobman WA, Wing DA, Newman RB, Wapner R, D’Alton ME et al (2018) Association of maternal obesity with longitudinal ultrasonographic measures of fetal growth: findings from the NICHD fetal growth studies-singletons. JAMA Pediatr 172(1):24–31
Marti A, Marcos A, Martinez JA (2001) Obesity and immune function relationships. Obes Rev 2(2):131–140
Vaisse C, Reiter JF, Berbari NF (2017) Cilia and obesity. Cold Spring Harb Perspect Biol 9(7):a028217
Scheja L, Heeren J (2019) The endocrine function of adipose tissues in health and cardiometabolic disease. Nat Rev Endocrinol 15(9):507–524
Louwen F, Ritter A, Kreis NN, Yuan J (2018) Insight into the development of obesity: functional alterations of adipose-derived mesenchymal stem cells. Obes Rev 19(7):888–904
Ritter A, Kreis NN, Louwen F, Yuan J (2020) Obesity and COVID-19: molecular mechanisms linking both pandemics. Int J Mol Sci 21(16):5793
Ritter A, Louwen F, Yuan J (2018) Deficient primary cilia in obese adipose-derived mesenchymal stem cells: obesity, a secondary ciliopathy? Obes Rev 19(10):1317–1328
Vaughan OR, Rosario FJ, Powell TL, Jansson T (2017) Regulation of placental amino acid transport and fetal growth. Prog Mol Biol Transl Sci 145:217–251
Jansson T, Powell TL (2013) Role of placental nutrient sensing in developmental programming. Clin Obstet Gynecol 56(3):591–601
Burton GJ, Fowden AL (2015) The placenta: a multifaceted, transient organ. Philos Trans R Soc Lond B Biol Sci 370(1663):20140066
Chuva de Sousa Lopes SM, Roelen BAJ, Lawson KA, Zwijsen A (1865) The development of the amnion in mice and other amniotes. Philos Trans R Soc Lond Ser B Biol Sci 2022(377):20210258
Kreis NN, Ritter A, Louwen F, Yuan J (2020) A message from the human placenta: structural and immunomodulatory defense against SARS-CoV-2. Cells 9(8):1777
Bayer A, Lennemann NJ, Ouyang Y, Bramley JC, Morosky S, Marques ET Jr, Cherry S, Sadovsky Y, Coyne CB (2016) Type III interferons produced by human placental trophoblasts confer protection against Zika virus infection. Cell Host Microbe 19(5):705–712
Turco MY, Moffett A (2019) Development of the human placenta. Development 146(22):dev163428
Arora N, Sadovsky Y, Dermody TS, Coyne CB (2017) Microbial vertical transmission during human pregnancy. Cell Host Microbe 21(5):561–567
O’Tierney-Ginn PF, Lash GE (2014) Beyond pregnancy: modulation of trophoblast invasion and its consequences for fetal growth and long-term children’s health. J Reprod Immunol 104–105:37–42
Knofler M, Haider S, Saleh L, Pollheimer J, Gamage T, James J (2019) Human placenta and trophoblast development: key molecular mechanisms and model systems. Cell Mol Life Sci 76(18):3479–3496
Barker DJ, Thornburg KL (2013) Placental programming of chronic diseases, cancer and lifespan: a review. Placenta 34(10):841–845
Eriksson JG, Kajantie E, Thornburg KL, Osmond C, Barker DJ (2011) Mother’s body size and placental size predict coronary heart disease in men. Eur Heart J 32(18):2297–2303
Thornburg KL (2011) Foetal programming reveals the dark side of AT(2)R. Cardiovasc Res 89(2):260–261
Goeden N, Velasquez J, Arnold KA, Chan Y, Lund BT, Anderson GM, Bonnin A (2016) Maternal inflammation disrupts fetal neurodevelopment via increased placental output of serotonin to the fetal brain. J Neurosci 36(22):6041–6049
Bonnin A, Goeden N, Chen K, Wilson ML, King J, Shih JC, Blakely RD, Deneris ES, Levitt P (2011) A transient placental source of serotonin for the fetal forebrain. Nature 472(7343):347–350
Howerton CL, Morgan CP, Fischer DB, Bale TL (2013) O-GlcNAc transferase (OGT) as a placental biomarker of maternal stress and reprogramming of CNS gene transcription in development. Proc Natl Acad Sci U S A 110(13):5169–5174
Mikaelsson MA, Constancia M, Dent CL, Wilkinson LS, Humby T (2013) Placental programming of anxiety in adulthood revealed by Igf2-null models. Nat Commun 4:2311
Fang J, Furesz TC, Lurent RS, Smith CH, Fant ME (1997) Spatial polarization of insulin-like growth factor receptors on the human syncytiotrophoblast. Pediatr Res 41(2):258–265
James-Allan LB, Arbet J, Teal SB, Powell TL, Jansson T (2019) Insulin stimulates GLUT4 trafficking to the syncytiotrophoblast basal plasma membrane in the human placenta. J Clin Endocrinol Metab 104(9):4225–4238
Ebenbichler CF, Kaser S, Laimer M, Wolf HJ, Patsch JR, Illsley NP (2002) Polar expression and phosphorylation of human leptin receptor isoforms in paired, syncytial, microvillous and basal membranes from human term placenta. Placenta 23(6):516–521
Kovo M, Zion-Saukhanov E, Schreiber L, Mevorach N, Divon M, Ben-Haroush A, Bar J (2015) The effect of maternal obesity on pregnancy outcome in correlation with placental pathology. Reprod Sci 22(12):1643–1648
Beneventi F, Bellingeri C, De Maggio I, Cavagnoli C, Fumanelli S, Ligari E, Fiandrino G, Cesari S, Spinillo A (2023) Placental pathologic features in obesity. Placenta 144:1–7
Leon-Garcia SM, Roeder HA, Nelson KK, Liao X, Pizzo DP, Laurent LC, Parast MM, LaCoursiere DY (2016) Maternal obesity and sex-specific differences in placental pathology. Placenta 38:33–40
Sood R, Zehnder JL, Druzin ML, Brown PO (2006) Gene expression patterns in human placenta. Proc Natl Acad Sci U S A 103(14):5478–5483
Scott NM, Hodyl NA, Murphy VE, Osei-Kumah A, Wyper H, Hodgson DM, Smith R, Clifton VL (2009) Placental cytokine expression covaries with maternal asthma severity and fetal sex. J Immunol 182(3):1411–1420
Myatt L, Maloyan A (2016) Obesity and placental function. Semin Reprod Med 34(1):42–49
Braun AE, Mitchel OR, Gonzalez TL, Sun T, Flowers AE, Pisarska MD, Winn VD (2022) Sex at the interface: the origin and impact of sex differences in the developing human placenta. Biol Sex Differ 13(1):50
Olney KC, Plaisier SB, Phung TN, Silasi M, Perley L, O’Bryan J, Ramirez L, Kliman HJ, Wilson MA (2022) Sex differences in early and term placenta are conserved in adult tissues. Biol Sex Differ 13(1):74
Hjort L, Novakovic B, Cvitic S, Saffery R, Damm P, Desoye G (2022) Placental DNA methylation in pregnancies complicated by maternal diabetes and/or obesity: state of the art and research gaps. Epigenetics 17(13):2188–2208
Lendvai A, Deutsch MJ, Plosch T, Ensenauer R (2016) The peroxisome proliferator-activated receptors under epigenetic control in placental metabolism and fetal development. Am J Physiol Endocrinol Metab 310(10):E797–E810
Vaughan OR, Fowden AL (2016) Placental metabolism: substrate requirements and the response to stress. Reprod Domest Anim 51(Suppl 2):25–35
Hellmuth C, Lindsay KL, Uhl O, Buss C, Wadhwa PD, Koletzko B, Entringer S (2017) Association of maternal prepregnancy BMI with metabolomic profile across gestation. Int J Obes 41(1):159–169
Saben J, Lindsey F, Zhong Y, Thakali K, Badger TM, Andres A, Gomez-Acevedo H, Shankar K (2014) Maternal obesity is associated with a lipotoxic placental environment. Placenta 35(3):171–177
Narapareddy L, Wildman DE, Armstrong DL, Weckle A, Bell AF, Patil CL, Tardif SD, Ross CN, Rutherford JN (2020) Maternal weight affects placental DNA methylation of genes involved in metabolic pathways in the common marmoset monkey (Callithrix jacchus). Am J Primatol 82(3):e23101
Shrestha D, Workalemahu T, Tekola-Ayele F (2019) Maternal dyslipidemia during early pregnancy and epigenetic ageing of the placenta. Epigenetics 14(10):1030–1039
Qiao L, Guo Z, Bosco C, Guidotti S, Wang Y, Wang M, Parast M, Schaack J, Hay WW Jr, Moore TR et al (2015) Maternal high-fat feeding increases placental lipoprotein lipase activity by reducing SIRT1 expression in mice. Diabetes 64(9):3111–3120
Lager S, Ramirez VI, Gaccioli F, Jang B, Jansson T, Powell TL (2016) Protein expression of fatty acid transporter 2 is polarized to the trophoblast basal plasma membrane and increased in placentas from overweight/obese women. Placenta 40:60–66
Segura MT, Demmelmair H, Krauss-Etschmann S, Nathan P, Dehmel S, Padilla MC, Rueda R, Koletzko B, Campoy C (2017) Maternal BMI and gestational diabetes alter placental lipid transporters and fatty acid composition. Placenta 57:144–151
Strakovsky RS, Pan YX (2012) A decrease in DKK1, a WNT inhibitor, contributes to placental lipid accumulation in an obesity-prone rat model. Biol Reprod 86(3):81
Liu L, Zhuang X, Jiang M, Guan F, Fu Q, Lin J (2017) ANGPTL4 mediates the protective role of PPARgamma activators in the pathogenesis of preeclampsia. Cell Death Dis 8(9):e3054
Fattuoni C, Mando C, Palmas F, Anelli GM, Novielli C, Parejo Laudicina E, Savasi VM, Barberini L, Dessi A, Pintus R et al (2018) Preliminary metabolomics analysis of placenta in maternal obesity. Placenta 61:89–95
Saben J, Zhong Y, Gomez-Acevedo H, Thakali KM, Borengasser SJ, Andres A, Shankar K (2013) Early growth response protein-1 mediates lipotoxicity-associated placental inflammation: role in maternal obesity. Am J Physiol Endocrinol Metab 305(1):E1–E14
Lassance L, Haghiac M, Leahy P, Basu S, Minium J, Zhou J, Reider M, Catalano PM, Hauguel-de Mouzon S (2015) Identification of early transcriptome signatures in placenta exposed to insulin and obesity. Am J Obstet Gynecol 212(5):647.e641–e611.
Barbour LA (2019) Metabolic culprits in obese pregnancies and gestational diabetes mellitus: big babies, big twists, big picture: the 2018 Norbert Freinkel Award Lecture. Diabetes Care 42(5):718–726
Barbour LA, Farabi SS, Friedman JE, Hirsch NM, Reece MS, Van Pelt RE, Hernandez TL (2018) Postprandial triglycerides predict newborn fat more strongly than glucose in women with obesity in early pregnancy. Obesity 26(8):1347–1356
Fowden AL, Camm EJ, Sferruzzi-Perri AN (2021) Effects of maternal obesity on placental phenotype. Curr Vasc Pharmacol 19(2):113–131
Sferruzzi-Perri AN, Camm EJ (2016) The programming power of the placenta. Front Physiol 7:33
Faas MM, De Vos P (2018) Innate immune cells in the placental bed in healthy pregnancy and preeclampsia. Placenta 69:125–133
Monaco-Brown M, Lawrence DA (2022) Obesity and maternal-placental-fetal immunology and health. Front Pediatr 10:859885
Challier JC, Basu S, Bintein T, Minium J, Hotmire K, Catalano PM, Hauguel-de Mouzon S (2008) Obesity in pregnancy stimulates macrophage accumulation and inflammation in the placenta. Placenta 29(3):274–281
Mele J, Muralimanoharan S, Maloyan A, Myatt L (2014) Impaired mitochondrial function in human placenta with increased maternal adiposity. Am J Physiol Endocrinol Metab 307(5):E419–E425
Laskewitz A, van Benthem KL, Kieffer TEC, Faas MM, Verkaik-Schakel RN, Plosch T, Scherjon SA, Prins JR (2019) The influence of maternal obesity on macrophage subsets in the human decidua. Cell Immunol 336:75–82
Kelley DE, He J, Menshikova EV, Ritov VB (2002) Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51(10):2944–2950
Lager S, Jansson N, Olsson AL, Wennergren M, Jansson T, Powell TL (2011) Effect of IL-6 and TNF-alpha on fatty acid uptake in cultured human primary trophoblast cells. Placenta 32(2):121–127
Abelius MS, Janefjord C, Ernerudh J, Berg G, Matthiesen L, Duchen K, Nilsson LJ, Jenmalm MC (2015) The placental immune milieu is characterized by a Th2- and anti-inflammatory transcription profile, regardless of maternal allergy, and associates with neonatal immunity. Am J Reprod Immunol 73(5):445–459
Myles IA, Fontecilla NM, Janelsins BM, Vithayathil PJ, Segre JA, Datta SK (2013) Parental dietary fat intake alters offspring microbiome and immunity. J Immunol 191(6):3200–3209
Forno E, Young OM, Kumar R, Simhan H, Celedon JC (2014) Maternal obesity in pregnancy, gestational weight gain, and risk of childhood asthma. Pediatrics 134(2):e535–e546
Harpsoe MC, Basit S, Bager P, Wohlfahrt J, Benn CS, Nohr EA, Linneberg A, Jess T (2013) Maternal obesity, gestational weight gain, and risk of asthma and atopic disease in offspring: a study within the Danish National Birth Cohort. J Allergy Clin Immunol 131(4):1033–1040
Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445
Pantham P, Aye IL, Powell TL (2015) Inflammation in maternal obesity and gestational diabetes mellitus. Placenta 36(7):709–715
Roberts KA, Riley SC, Reynolds RM, Barr S, Evans M, Statham A, Hor K, Jabbour HN, Norman JE, Denison FC (2011) Placental structure and inflammation in pregnancies associated with obesity. Placenta 32(3):247–254
Pathmaperuma AN, Mana P, Cheung SN, Kugathas K, Josiah A, Koina ME, Broomfield A, Delghingaro-Augusto V, Ellwood DA, Dahlstrom JE et al (2010) Fatty acids alter glycerolipid metabolism and induce lipid droplet formation, syncytialisation and cytokine production in human trophoblasts with minimal glucose effect or interaction. Placenta 31(3):230–239
Aye IL, Waddell BJ, Mark PJ, Keelan JA (2012) Oxysterols exert proinflammatory effects in placental trophoblasts via TLR4-dependent, cholesterol-sensitive activation of NF-kappaB. Mol Hum Reprod 18(7):341–353
Roberts VH, Smith J, McLea SA, Heizer AB, Richardson JL, Myatt L (2009) Effect of increasing maternal body mass index on oxidative and nitrative stress in the human placenta. Placenta 30(2):169–175
Basu S, Haghiac M, Surace P, Challier JC, Guerre-Millo M, Singh K, Waters T, Minium J, Presley L, Catalano PM et al (2011) Pregravid obesity associates with increased maternal endotoxemia and metabolic inflammation. Obesity 19(3):476–482
Shirasuna K, Seno K, Ohtsu A, Shiratsuki S, Ohkuchi A, Suzuki H, Matsubara S, Nagayama S, Iwata H, Kuwayama T (2016) AGEs and HMGB1 increase inflammatory cytokine production from human placental cells, resulting in an enhancement of monocyte migration. Am J Reprod Immunol 75(5):557–568
Yang X, Li M, Haghiac M, Catalano PM, O’Tierney-Ginn P, Hauguel-de Mouzon S (2016) Causal relationship between obesity-related traits and TLR4-driven responses at the maternal-fetal interface. Diabetologia 59(11):2459–2466
Liong S, Barker G, Lappas M (2018) Placental Ras regulates inflammation associated with maternal obesity. Mediators Inflamm 2018:3645386
Myatt L, Cui X (2004) Oxidative stress in the placenta. Histochem Cell Biol 122(4):369–382
Farley D, Tejero ME, Comuzzie AG, Higgins PB, Cox L, Werner SL, Jenkins SL, Li C, Choi J, Dick EJ Jr et al (2009) Feto-placental adaptations to maternal obesity in the baboon. Placenta 30(9):752–760
Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39(1):44–84
Al-Gubory KH, Fowler PA, Garrel C (2010) The roles of cellular reactive oxygen species, oxidative stress and antioxidants in pregnancy outcomes. Int J Biochem Cell Biol 42(10):1634–1650
Hastie R, Lappas M (2014) The effect of pre-existing maternal obesity and diabetes on placental mitochondrial content and electron transport chain activity. Placenta 35(9):673–683
Malti N, Merzouk H, Merzouk SA, Loukidi B, Karaouzene N, Malti A, Narce M (2014) Oxidative stress and maternal obesity: feto-placental unit interaction. Placenta 35(6):411–416
Martino J, Sebert S, Segura MT, Garcia-Valdes L, Florido J, Padilla MC, Marcos A, Rueda R, McArdle HJ, Budge H et al (2016) Maternal body weight and gestational diabetes differentially influence placental and pregnancy outcomes. J Clin Endocrinol Metab 101(1):59–68
Marin R, Chiarello DI, Abad C, Rojas D, Toledo F, Sobrevia L (2020) Oxidative stress and mitochondrial dysfunction in early-onset and late-onset preeclampsia. Biochim Biophys Acta 1866(12):165961
Gusar V, Ganichkina M, Chagovets V, Kan N, Sukhikh G (2020) MiRNAs regulating oxidative stress: a correlation with doppler sonography of uteroplacental complex and clinical state assessments of newborns in fetal growth restriction. J Clin Med 9(10):3227
Haghiac M, Basu S, Presley L, Serre D, Catalano PM, Hauguel-de Mouzon S (2014) Patterns of adiponectin expression in term pregnancy: impact of obesity. J Clin Endocrinol Metab 99(9):3427–3434
Nogues P, Dos Santos E, Jammes H, Berveiller P, Arnould L, Vialard F, Dieudonne MN (2019) Maternal obesity influences expression and DNA methylation of the adiponectin and leptin systems in human third-trimester placenta. Clin Epigenetics 11(1):20
Shrestha D, Ouidir M, Workalemahu T, Zeng X, Tekola-Ayele F (2020) Placental DNA methylation changes associated with maternal prepregnancy BMI and gestational weight gain. Int J Obes 44(6):1406–1416
Shen WB, Ni J, Yao R, Goetzinger KR, Harman C, Reece EA, Wang B, Yang P (2022) Maternal obesity increases DNA methylation and decreases RNA methylation in the human placenta. Reprod Toxicol 107:90–96
Fernandez-Jimenez N, Fore R, Cilleros-Portet A, Lepeule J, Perron P, Kvist T, Tian FY, Lesseur C, Binder AM, Lozano M et al (2022) A meta-analysis of pre-pregnancy maternal body mass index and placental DNA methylation identifies 27 CpG sites with implications for mother-child health. Commun Biol 5(1):1313
Gomez-Vilarrubla A, Mas-Pares B, Carreras-Badosa G, Xargay-Torrent S, Prats-Puig A, Bonmati-Santane A, de Zegher F, Ibanez L, Lopez-Bermejo A, Bassols J (2023) Placental epigenetic marks related to gestational weight gain reveal potential genes associated with offspring obesity parameters. Obesity 31(7):1903–1912
Jarvie E, Hauguel-de-Mouzon S, Nelson SM, Sattar N, Catalano PM, Freeman DJ (2010) Lipotoxicity in obese pregnancy and its potential role in adverse pregnancy outcome and obesity in the offspring. Clin Sci 119(3):123–129
Dalrymple KV, Thompson JMD, Begum S, Godfrey KM, Poston L, Seed PT, McCowan LME, Wall C, Shelling A, North R et al (2019) Relationships of maternal body mass index and plasma biomarkers with childhood body mass index and adiposity at 6 years: the children of SCOPE study. Pediatr Obes 14(10):e12537
Kadakia R, Zheng Y, Zhang Z, Zhang W, Hou L, Josefson JL (2017) Maternal pre-pregnancy BMI downregulates neonatal cord blood LEP methylation. Pediatr Obes 12(Suppl 1):57–64
Beceheli I, Horvaticek M, Peric M, Nikolic B, Holuka C, Klasic M, Ivanisevic M, Starcevic M, Desoye G, Hranilovic D et al (2024) Methylation of serotonin regulating genes in cord blood cells: association with maternal metabolic parameters and correlation with methylation in peripheral blood cells during childhood and adolescence. Clin Epigenetics 16(1):4
Jonsson J, Renault KM, Perfilyev A, Vaag A, Carlsen EM, Norgaard K, Franks PW, Ling C (2023) Gestational weight gain in pregnant women with obesity is associated with cord blood DNA methylation, which partially mediates offspring anthropometrics. Clin Transl Med 13(3):e1215
Ma Z, Wang Y, Quan Y, Wang Z, Liu Y, Ding Z (2022) Maternal obesity alters methylation level of cytosine in CpG island for epigenetic inheritance in fetal umbilical cord blood. Hum Genomics 16(1):34
Meir AY, Huang W, Cao T, Hong X, Wang G, Pearson C, Adams WG, Wang X, Liang L (2023) Umbilical cord DNA methylation is associated with body mass index trajectories from birth to adolescence. EBioMedicine 91:104550
Jonsson J, Renault KM, Garcia-Calzon S, Perfilyev A, Estampador AC, Norgaard K, Lind MV, Vaag A, Hjort L, Michaelsen KF et al (2021) Lifestyle intervention in pregnant women with obesity impacts cord blood DNA methylation, which associates with body composition in the offspring. Diabetes 70(4):854–866
Dumolt J, Powell TL, Jansson T, Rosario FJ (2022) Normalization of maternal adiponectin in obese pregnant mice prevents programming of impaired glucose metabolism in adult offspring. FASEB J 36(7):e22383
Vaughan OR, Rosario FJ, Powell TL, Jansson T (2020) Normalisation of circulating adiponectin levels in obese pregnant mice prevents cardiac dysfunction in adult offspring. Int J Obes 44(2):488–499
Cirulli F, De Simone R, Musillo C, Ajmone-Cat MA, Berry A (2022) Inflammatory signatures of maternal obesity as risk factors for neurodevelopmental disorders: role of maternal microbiota and nutritional intervention strategies. Nutrients 14(15):3150
Tang M, Marroquin E (2022) The role of the gut microbiome in the intergenerational transmission of the obesity phenotype: a narrative review. Front Med 9:1057424
Strobel KM, Juul SE, Hendrixson DT (2023) Maternal nutritional status and the microbiome across the pregnancy and the post-partum period. Microorganisms 11(6):1569
Kearns ML, Reynolds CM (2023) Developmentally programmed obesity: is there a role for anti-inflammatory nutritional strategies? Exp Physiol
Phillips EA, Hendricks N, Bucher M, Maloyan A (2022) Vitamin D supplementation improves mitochondrial function and reduces inflammation in placentae of obese women. Front Endocrinol 13:893848
Sheng K, Cao W, Niu Y, Deng Q, Zong C (2017) Effective detection of variation in single-cell transcriptomes using MATQ-seq. Nat Methods 14(3):267–270
Rafiee MR, Girardot C, Sigismondo G, Krijgsveld J (2016) Expanding the circuitry of pluripotency by selective isolation of chromatin-associated proteins. Mol Cell 64(3):624–635
Okae H, Toh H, Sato T, Hiura H, Takahashi S, Shirane K, Kabayama Y, Suyama M, Sasaki H, Arima T (2018) Derivation of human trophoblast stem cells. Cell Stem Cell 22(1):50–63.e56
Haider S, Meinhardt G, Saleh L, Kunihs V, Gamperl M, Kaindl U, Ellinger A, Burkard TR, Fiala C, Pollheimer J et al (2018) Self-renewing trophoblast organoids recapitulate the developmental program of the early human placenta. Stem Cell Rep 11(2):537–551
Turco MY, Gardner L, Kay RG, Hamilton RS, Prater M, Hollinshead MS, McWhinnie A, Esposito L, Fernando R, Skelton H et al (2018) Trophoblast organoids as a model for maternal-fetal interactions during human placentation. Nature 564(7735):263–267
Romberg SI, Kreis NN, Friemel A, Roth S, Souto AS, Hoock SC, Fischer K, Nowak T, Solbach C, Louwen F et al (2022) Human placental mesenchymal stromal cells are ciliated and their ciliation is compromised in preeclampsia. BMC Med 20(1):35
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FL and JY conceptualized the manuscript and searched related data. JY prepared the initial draft. FL, NNK and AR did critical reading. AR drew the figure. All authors have read and approved the manuscript.
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Louwen, F., Kreis, NN., Ritter, A. et al. Maternal obesity and placental function: impaired maternal–fetal axis. Arch Gynecol Obstet 309, 2279–2288 (2024). https://doi.org/10.1007/s00404-024-07462-w
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DOI: https://doi.org/10.1007/s00404-024-07462-w