Placental Nutrient Transport Research Articles

Influence of Maternal Adipokines on Anthropometry, Adiposity, and Neurodevelopmental Outcomes of the Offspring.

Pregnancy is distinguished by a multitude of intricate interactions between the mother and the new individual, commencing at implantation and persisting until the maturation and integration of the fetal apparatus and systems. The physiological increase in fat mass during pregnancy and the association of maternal obesity with adverse neonatal outcomes have directed attention to the study of maternal adipokines as participants in fetal development. Interestingly, maternal concentrations of certain adipokines such as adiponectin, leptin, tumor necrosis factor-alpha, and interleukin-6 have been found to be associated with offspring anthropometry and adiposity at birth and at three months of age, even with neurodevelopmental alterations later in life. This is partly explained by the functions of these adipokines in the regulation of maternal metabolism and placental nutrient transport. This review compiles, organizes, and analyzes the most relevant studies on the association between maternal adipokines with anthropometry, adiposity, and neurodevelopmental outcomes of the offspring. Furthermore, it proposes the underlying mechanisms involved in this association.

Trophoblast-specific overexpression of adiponectin receptor 2 causes fetal growth restriction in pregnant mice.

Maternal obesity in pregnancy is strongly associated with complications such as fetal overgrowth and infants of obese mothers have an increased risk to develop obesity, diabetes, and cardiovascular disease later in life. However, the underlying mechanisms are not well established. Circulating levels of adiponectin are low in obese pregnant women and maternal circulating adiponectin is negatively associated with birth weight. We have reported that normalizing maternal adiponectin in obese pregnant mice prevents placental dysfunction, fetal overgrowth, and programming of offspring cardio-metabolic disease. However, the mechanistic link between maternal adiponectin, placental function, and fetal growth remains to be established. We hypothesized that trophoblast-specific overexpression of the adiponectin receptor 2 (Adipor2) in healthy pregnant mice inhibits placental mTORC1 signaling and nutrient transport, resulting in fetal growth restriction. Using lentiviral transduction of blastocysts with a mammalian gene expression lentiviral vector for up-regulation of Adipor2 (Adipor2-OX), we achieved a ~ 3-fold increase in placenta Adipor2 mRNA levels and a 2-fold increase of the ADIPOR2 protein in the trophoblast plasma membrane. Placenta-specific Adipor2-OX increased placental peroxisome proliferator-activated receptor-α phosphorylation, ceramide synthase expression and ceramide concentrations. Furthermore, Adipor2-OX inhibited placental mTORC1 signaling and reduced invivo placental transport of glucose and amino acids. Lastly, Adipor2-OX reduced fetal weight by 11%. These data provide mechanistic evidence that placental Adipor2 signaling directly affects fetal growth. We propose that low circulating adiponectin in maternal obesity causes fetal overgrowth and programs the offspring for cardio-metabolic disease mediated by a direct effect on placental function.

Methionine supply during mid-gestation modulates the bovine placental mTOR pathway, nutrient transporters, and offspring birth weight in a sex-specific manner.

The mechanistic target of rapamycin (mTOR) predominantly regulates the expression and activity of placental nutrient transporters. The mTOR pathway can be activated by several nutrients, including the essential amino acid methionine. Additionally, previous research in nonruminant animals suggests that mTOR is influenced in a sexually dimorphic manner. In bovine, there is limited understanding of how maternal nutrition and offspring sexual dimorphism affect the placental transfer of nutrients. Thus, we investigated the effects of increasing the supply of dietary methionine to beef cattle heifers during mid-gestation on mTOR signaling, placental nutrient transporters, and fetal growth in male and female offspring. Forty purebred Angus heifers were used in a randomized complete block design experiment. From day 90 to 180 of gestation, heifers received a basal diet with no added methionine (CON, n = 20), or the basal diet plus 8.3g of rumen-protected methionine (MET, n = 20) per animal daily. All animals received a basal diet in the first and third trimesters of gestation. Cotyledonary tissue samples were collected at parturition and utilized to examine the mTOR pathway and nutrient transporters through protein and gene expression analysis. The offspring's body weight was measured at birth. Data were analyzed using a mixed model that included the fixed effect of treatment, offspring sex, their interactions, and the random effect of block. At day 170 of gestation, MET-supplemented heifers showed higher plasma concentrations of methionine and glutamate (P < 0.01) and lower glycine and proline levels (P ≤ 0.01) compared to the CON group. A treatment × sex interaction was observed for calf birth weight (P = 0.03). In heifers that delivered male calves, MET supplementation increased the birth weight of the calves (P < 0.01). However, the dietary treatments had no effect on the birth weight of female calves (P = 0.32). The increase in birth weight of male calves from MET-fed heifers resembles with the upregulation of placental mTOR and phosphorylated mTOR (P ≤ 0.03), as well as the amino acid transporters SLC1A5, SLC7A5, SLC38A6, and SLC38A11, and the glucose transporters SLC2A1 and SLC2A8 (P ≤ 0.05). Our findings suggest that increasing the supply of methionine to beef heifers during mid-gestation can modulate placental nutrient transport and fetal growth in a sex-dependent manner and that these effects are mediated, at least in part, by the mTOR pathway.

Dietary supplementation with pterostilbene activates the PI3K-AKT-mTOR signalling pathway to alleviate progressive oxidative stress and promote placental nutrient transport

BackgroundProgressive oxidative stress easily occurs as a result of a gradual increase in the intensity of maternal metabolism due to rapid foetal development and increased intensity of lactation. However, studies on the effects of processive oxidative stress on nutrient transport in the placenta have received little attention. The present study was conducted on sows at 85 days of gestation to study the effects of pterostilbene (PTE) on maternal oxidative stress status and placental nutrient transport.ResultsPTE increased the antioxidant capacity and immunoglobulin content in mothers’ blood and milk, reduced the level of inflammatory factors, and improved the nutrient content of milk. PTE also reduced sow backfat loss and the number of weak sons, and increased piglet weaning weight and total weaning litter weight. We subsequently found that PTE enhanced placental glucose and fatty acid transport and further affected glycolipid metabolism by increasing the expression of LAL, PYGM, and Gbe-1, which activated the PI3K phosphorylation pathway. Moreover, PTE addition altered the relative abundance of the Firmicutes, Proteobacteria, Parabacillus, and Bacteroidetes-like RF16 groups in sow faeces. PTE increased the levels of acetate, propionate, butyrate and isovalerate in the faeces.ConclusionsThese findings reveal that the addition of PTE during pregnancy and lactation mitigates the effects of processive oxidative stress on offspring development by altering maternal microbial and placental nutrient transport capacity.Graphical

Placental Transport of Amino Acids in Rats with Methionine-Induced Hyperhomocysteinemia.

Maternal hyperhomocysteinemia (HHcy) is a risk factor for intrauterine growth restriction presumably caused by a decrease in the placental transport of nutrients. We investigated the effect of experimental HHcy induced by daily methionine administration to pregnant rats on the free amino acid levels in the maternal and fetal blood, as well as on morphological and biochemical parameters associated with the amino acid transport through the placenta. HHcy caused an increase in the levels of most free amino acids in the maternal blood on gestational day 20, while the levels of some amino acids in the fetal blood were decreased. In rats with HHcy, the maternal sinusoids in the placental labyrinth were narrowed, which was accompanied by aggregation of red blood cells. We also observed an increase in the neutral amino acid transporters (LAT1, SNAT2) protein levels and activation of 4E-BP1, a downstream effector of mTORC1 complex, in the labyrinth zone. Maternal HHcy affected the placental barrier permeability, as evidenced by intensification of the mother-to-fetus transfer of Evans Blue dye. The imbalance in the free amino acid levels in the maternal and fetal blood in HHcy may be due to the competition of homocysteine with other amino acids for common transporters, as well as a decrease in the area of exchange zone between maternal and fetal circulations in the placental labyrinth. Upregulation of the neutral amino acid transporter expression in the labyrinth zone may be a compensatory response to an insufficient intrauterine amino acid supply and fetal growth restriction.

Hypoglycaemia in screening oral glucose tolerance test in pregnancy with low birth weight fetus.

Maternal hypoglycemia, a condition characterized by lower than normal blood glucose levels in pregnant women, has been increasingly associated with adverse pregnancy outcomes, including low birth weight (LBW) in neonates. LBW, defined as a birth weight of less than 2500 g, can result from various factors, including maternal nutrition, health status, and metabolic conditions like hypoglycemia. Maternal hypoglycemia may affect fetal growth by altering the supply of essential nutrients and oxygen to the fetus, leading to restricted fetal development and growth. This condition poses significant risks not only during pregnancy but also for the long-term health of the child, increasing the likelihood of developmental delays, health issues, and chronic conditions later in life. Research in this area has focused on understanding the mechanisms through which maternal hypoglycemia influences fetal development, with studies suggesting that alterations in placental blood flow and nutrient transport, as well as direct effects on fetal insulin levels and metabolism, may play a role. Given the potential impact of maternal hypoglycemia on neonatal health outcomes, early detection and management are crucial to minimize risks for LBW and its associated complications. Further investigations are needed to fully elucidate the complex interactions between maternal glucose levels and fetal growth, as well as to develop targeted interventions to support the health of both mother and child. Understanding these relationships is vital for improving prenatal care and outcomes for pregnancies complicated by hypoglycemia.

Dietary Supplementation with 25-Hydroxyvitamin D3 on Reproductive Performance and Placental Oxidative Stress in Primiparous Sows during Mid-to-Late Gestation.

The placenta plays a crucial role in nutrient transport and waste exchange between the dam and fetus, sustaining fetal growth. While the positive effects of 25-hydroxyvitamin D3 (25-OH-D3) on animal performance have been reported, its impact on placental function remains largely unknown. Therefore, this study aimed to investigate the effects of supplementing 25-OH-D3 in the diet of primiparous sows on reproductive performance, antioxidant capacity, placental oxidative stress, nutrient transport, and inflammatory response during mid-to-late gestation. A total of 45 healthy Landrace × Yorkshire primiparous sows on day 60 of gestation were selected and randomly allocated to three treatment groups based on body weight and backfat thickness: the control group (corn-soybean meal basal diet), the VD3 group (basal diet + 2000 IU VD3), and the 25-OH-D3 group (basal diet + 50 μg/kg 25-OH-D3). The results demonstrated that supplementation with 25-OH-D3 in the diet enhanced sows' average litter weight and birth weight during mid-to-late gestation. Additionally, plasma malondialdehyde (MDA) concentrations in sows significantly decreased in the VD3 and 25-OH-D3 groups (p < 0.05). Furthermore, lower gene expressions of placental HO-1, GPX2, IL-8, and IL-6 were found in the VD3 or 25-OH-D3 groups (p < 0.05 or p < 0.10), while higher gene expressions of GLUT1 and SNAT2 in the placenta of sows were observed in the VD3 and 25-OH-D3 groups, respectively (p < 0.05). These findings indicate that the supplementation of VD3 and 25-OH-D3 in the diet of sows can improve their plasma oxidative stress status, enhance placental antioxidant capacity and nutrient transport, and reduce placental inflammatory responses, with more pronounced improvements in sow performance observed in sows fed diets supplemented with 25-OH-D3.

Adiponectin and Leptin during Pregnancy: A Systematic Review of Their Association with Pregnancy Disorders, Fetal Growth and Placental Function

During pregnancy, the adipokines leptin and adiponectin can affect placental nutrient transport and inflammatory pathways, potentially leading to altered fetal growth and pregnancy complications including gestational diabetes mellitus (GDM) and preeclampsia (PE). The aim of this systematic review is to gather and analyze research on maternal circulating leptin and adiponectin levels and their relationship to adverse pregnancy and birth outcomes. Additionally, it seeks to determine whether these hormones are linked to alterations in placental transporters and cell signaling pathways. PubMed and MEDLINE were systematically searched to include studies published between 2012 and 2022. All primary data studies reporting serum adiponectin and/or leptin, placental mRNA and protein levels of related transporters, and adverse birth outcomes were eligible. The current systematic review encompasses a total of 14 articles. Abnormal serum maternal leptin and adiponectin levels were associated with changes in fetal growth and placental cellular signaling and nutrient transporters. A majority of studies associated elevated maternal leptin and reduced adiponectin with fetal overgrowth, although this relationship was not consistent and may be complicated when other pathologies are present. The effects of maternal leptin and adiponectin on fetal growth may be driven by placental adaptation in nutrient transporters and mitochondria. Future studies should determine if the placental effects of leptin and adiponectin that have been found in models have mechanistic roles in human pregnancy.

Assessing the expression of placental nutrient transporters following teratogenic valproic acid exposure in CD-1 mice.

Assessing the expression of placental nutrient transporters following teratogenic valproic acid exposure in CD-1 mice.

Omega-3 reverses the metabolic and epigenetically regulated placental phenotype acquired from preconceptional and peri-conceptional exposure to air pollutants

Air pollution is detrimental to pregnancy adversely affecting maternal and child health. Our objective was to unravel epigenetic mechanisms mediating the effect of preconception, periconception, and gestational exposure to inhaled air pollutants (AP) upon the maternal and placental-fetal phenotype and explore the benefit of an omega-3 rich dietary intervention. To this end, we investigated intranasal instilled AP during 8 weeks of preconception, periconception, and gestation (G; D0 to 18) upon GD16-19 maternal mouse metabolic status, placental nutrient transporters, placental-fetal size, and placental morphology. Prepregnant mice were glucose intolerant and insulin resistant, while pregnant mice were glucose intolerant but displayed no major placental macro-nutrient transporter changes, except for an increase in CD36. Placentas revealed inflammatory cellular infiltration with cellular edema, necrosis, hemorrhage, and an increase in fetal body weight. Upon examination of placental genome-wide epigenetic processes of DNA sequence specific 5′-hydroxymethylation (5′-hmC) and 5′-methylation (5′-mC) upon RNA sequenced gene expression profiles, revealed changes in key metabolic, inflammatory, transcriptional, and cellular processing genes and pathways. An omega-3 rich anti-inflammatory diet from preconception (8 weeks) through periconception and gestation (GD0-18), ameliorated all these maternal and placental-fetal adverse effects. We conclude that preconceptional, periconceptional and gestational exposures to AP incite a maternal inflammatory response resulting in features of pre-existing maternal diabetes mellitus with injury to the placental-fetal unit. DNA 5′-mC more than 5′-hmC mediated AP induced maternal inflammatory and metabolic dysregulation which together alter placental gene expression and phenotype. A dietary intervention partially reversing these adversities provides possibilities for a novel nutrigenomic therapeutic strategy.

A genetically small fetus impairs placental adaptations near term.

The placenta is a gatekeeper between the mother and fetus, adapting its structure and functions to support optimal fetal growth. Studies exploring adaptations of placentae that support the development of genetically small fetuses are lacking. Here, using a mouse model of impaired fetal growth, achieved by deleting insulin-like growth factor 2 (Igf2) in the epiblast, we assessed placental nutrient transfer and umbilical artery (UA) blood flow during late gestation. At embryonic day (E) 15.5, we observed a decline in the trans-placental flux of glucose and system A amino acids (by using 3H-MeG and 14C-MeAIB), proportionate to the diminished fetal size, whereas UA blood flow was normal. However, at E18.5, the trans-placental flux of both tracers was disproportionately decreased and accompanied by blunted UA blood flow. Feto-placental growth and nutrient transfer were more impaired in female conceptuses. Thus, reducing the fetal genetic demand for growth impairs the adaptations in placental blood flow and nutrient transport that normally support the fast fetal growth during late gestation. These findings have important implications for our understanding of the pathophysiology of pregnancies afflicted by fetal growth restriction.

Circular RNAs mediate the regulation of maternal placental nutrient transport and fetal development by sugar-sweetened beverages

Epidemiological and experimental studies have demonstrated a strong association between maternal diet and fetal birth weight, obesity, and metabolic syndrome. We investigated the pathways and modes of action of circular RNAs (circRNAs) that mediate the regulation of maternal reproductive performance and fetal development by sugar-sweetened beverages (20 % sucrose water, SSBs) using C57BL/6J mice as a model. Results showed that SSBs significantly increased the reproductive performance (P<0.05), body weight (P<0.01), fetal birth weight (P<0.05), placental weight (P<0.01), and the expression of nutrient transporter genes in the placenta and fetal liver (P<0.05), mainly by accelerating the maternal energy metabolism during pregnancy. However, maternal serum biochemical indices, antioxidant indices, and pathological damage to the liver and placenta predicted that the mother would be at greater health risks during this period. Moreover, transcriptomics results indicated that the differentially expressed (DE) circRNAs in the placenta regulate the maternal multiple metabolic pathways and the placental nutrient transport efficiency by sponging miRNAs and forming growth factors and proteins, ultimately improving the maternal reproductive performance. In addition, we verified the reliability of the sequencing results using reverse transcription polymerase chain reaction and identified the possibility of DE circRNAs binding to nutrient transporter genes using targeting relationship prediction. Finally, we constructed a correlation network that regulates maternal placental nutrient transport based on DE circRNAs, targeted miRNAs and nutrient transport-related genes. This study will provide scientific dietary guidance for pregnant women and new research ideas for preventing and treating pregnancy complications.

Gestational exposure to air pollutants perturbs metabolic and placenta-fetal phenotype

Air pollution (AP) is detrimental to pregnancies including increasing risk factors of gestational diabetes mellitus. We hypothesized that exposure to AP causes cardiovascular and metabolic disruption thereby altering placental gene expression, which in turn affects the placental phenotype and thereby embryonic/fetal development. To test this hypothesis, we investigated the impact of intra-nasal instilled AP upon gestational day 16–19 maternal mouse cardiovascular and metabolic status, placental nutrient transporters, and placental-fetal size and morphology. To further unravel mechanisms, we also examined placental total DNA 5’-hydroxymethylation and bulk RNA sequenced gene expression profiles. AP exposed pregnant mice and fetuses were tachycardic with a reduction in maternal left ventricular fractional shortening and increased uterine artery with decreased umbilical artery systolic peak velocities. In addition, they were hyperglycemic, glucose intolerant and insulin resistant, with changes in placental glucose (Glut3) and fatty acid (Fatp1 & Cd36) transporters, and a spatial disruption of cells expressing Glut10 that imports L-dehydroascorbic acid in protecting against oxidative stress. Placentas revealed inflammatory cellular infiltration with associated cellular edema and necrosis, with dilated vascular spaces and hemorrhage. Placental and fetal body weights decreased in mid-gestation with a reduction in brain cortical thickness emerging in late gestation. Placental total DNA 5’-hydroxymethylation was 2.5-fold higher, with perturbed gene expression profiles involving key metabolic, inflammatory, transcriptional, cellular polarizing and processing genes and pathways. We conclude that gestational exposure to AP incites a maternal inflammatory response resulting in features mimicking maternal gestational diabetes mellitus with altered placental DNA 5’-hydroxymethylation, gene expression, and associated injury.

Sex-specific effect of antenatal Zika virus infection on murine fetal growth, placental nutrient transporters, and nutrient sensor signaling pathways.

Maternal Zika virus (ZIKV) infection during pregnancy has been associated with severe intrauterine growth restriction (IUGR), placental damage, metabolism disturbances, and newborn neurological abnormalities. Here, we investigated the impact of maternal ZIKV infection on placental nutrient transporters and nutrient-sensitive pathways. Immunocompetent (C57BL/6) mice were injected with Low (103 PFU-ZIKVPE243) or High (5 × 107 PFU-ZIKVPE243) ZIKV titers at gestational day (GD) 12.5, and tissue was collected at GD18.5 (term). Fetal-placental growth was impaired in male fetuses, which exhibited higher placental expression of the ZIKV infective marker, eukaryotic translation initiation factor 2 (eIF2α), but lower levels of phospho-eIF2α. There were no differences in fetal-placental growth in female fetuses, which exhibited no significant alterations in placental ZIKV infective markers. Furthermore, ZIKV promoted increased expression of glucose transporter type 1 (Slc2a1/Glut1) and decreased levels of glucose-6-phosphate in female placentae, with no differences in amino acid transport potential. In contrast, ZIKV did not impact glucose transporters in male placentae but downregulated sodium-coupled neutral amino acid 2 (Snat2) transporter expression. We also observed sex-dependent differences in the hexosamine biosynthesis pathway (HBP) and O-GlcNAcylation in ZIKV-infected pregnancies, showing that ZIKV can disturb placental nutrient sensing. Our findings highlight molecular alterations in the placenta caused by maternal ZIKV infection, shedding light on nutrient transport, sensing, and availability. Our results also suggest that female and male placentae employ distinct coping mechanisms in response to ZIKV-induced metabolic changes, providing insights into therapeutic approaches for congenital Zika syndrome.

Fetal Origin of Abnormal Glucose Tolerance in Adult Offspring Induced by Maternal Bisphenol A Analogs Exposure.

With the widespread use of bisphenol A (BPA) analogs, their health risks have attracted attention. The effects of maternal BPA analogs exposure on glucose homeostasis in adult offspring and the underlying fetal origins require further exploration. Herein, we exposed pregnant mice to two types of BPA analogs─BPB and BPAF; we evaluated glucose homeostasis in adult offspring and maternal-fetal glucose transport by testing intraperitoneal glucose tolerance, determining glucose and glycogen contents, conducting positron emission tomography (PET)/computed tomography (CT), detecting expression of placental nutrient transport factors, and assessing placental barrier status. We observed that adult female offspring maternally exposed to BPB and BPAF exhibited low fasting blood glucose in adulthood, with even abnormal glucose tolerance in the BPAF group. This phenomenon can be traced back to the elevated fetal glucose induced by the increased efficiency of placenta glucose transport in late pregnancy. On the other hand, the expression of genes associated with vascular development and glucose transport was significantly altered in the placenta in the BPAF group, potentially contributing to enhanced fetal glucose. These findings provide preliminary insights into potential mechanisms underlying the disturbance of glucose metabolism in adult female offspring mice induced by maternal exposure to BPA analogs.

In Utero Overnutrition Influences Placental Nutrient Transport and Fetal Overgrowth

Obesity is defined as a body mass index (BMI) ≥30 kg/m2. Forty-three percent of women of childbearing age are obese, with a greater prevalence noted in Black women. Obesity increases the risk of diabetes (Type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM)). Obesity and diabetes are chronic states of overnutrition and metabolic dysregulation, each associated with an increased risk of macrosomia (large weight for gestational age in offspring). Macrosomia not only increases pregnancy complications but also increases the risk of metabolic disorders throughout the lifespan of the offspring. Fetal growth in utero is mediated by the nutritional environment and nutritional transport across the placenta. Maternal-fetal nutrient transport is primarily mediated by placental transporters for glucose, amino acids, free fatty acids, and cholesterol in the syncytiotrophoblast of the placenta. Yet, the mechanistic pathway driving fetal overgrowth in environments of overnutrition are not well defined. Therefore, we will test the hypothesis that diabetes (T2DM or GDM) exacerbates placental nutrient transport and fetal overgrowth in Black pregnant women with obesity. To evaluate the combined influence of obesity and diabetes (T2DM or GDM) on fetal growth, we evaluated n=100 electronic medical records of Black obese women with and without diabetes (T2DM or GDM) from 2012-2022 at the University of Mississippi Medical Center (UMMC). These women were singleton pregnancies with no additional underlying conditions. Gestational age of offspring and maternal age were similar among all groups. This study was approved by the Institutional Review Board at UMMC (IRB-UMMC-2021-0455). We found that Black obese women with diabetes (n=43) had higher BMIs compared to Black women with obesity alone (n=57) (43.50 ± 4.76 kg/m2 vs. 39.19 ± 3.48 kg/m2) (p&lt;0.05), indicating that obesity increases risk of diabetes in Black pregnant women. Additionally, offspring from Black obese women with diabetes had elevated birthweight compared to offspring from women with obesity alone (3345 ± 614.6 g vs. 3099 ± 465.4 g; p&lt;0.05). Male offspring from Black obese women with diabetes had elevated birthweight (3460 ± 695.8 g) compared to female offspring from Black obese women without diabetes (3068 ± 439.8 g) (p&lt;0.05), suggesting the maternal nutritional environment influences males more than females. Yet, the type of diabetes, T2DM or GDM, did not influence birthweight in offspring from Black obese women (T2DM: 3412 ± 743.5 g vs GDM: 3271 ± 439.7 g). To evaluate the influence of obesity plus diabetes on placental nutrient transport, we measured placental protein expression of glucose transporter-1 (Glut-1), a primary glucose transporter in the placenta, in a separate subset of placental tissue from Black obese women with and without diabetes (IRB-UMMC-2019-0058). Protein expression of Glut-1 was increased in placental tissue from Black women with obesity and diabetes (n=4) compared to Black women with obesity alone (n=4) (20.38 ± 5.87 A.U. vs. 9.41 ± 1.46 A.U.; p&lt;0.05). However, BMI was elevated in the group of women with obesity and diabetes compared to obesity alone (49.565 ± 1.39 kg/m2 vs. 43.44 ± 2.44 kg/m2; p&lt;0.05), again indicating that obesity increases risks of diabetes in Black pregnant women. This study indicates that combined obesity with diabetes during pregnancy is associated with increased birthweight and placental protein expression of Glut-1. Additional studies are warranted to decipher the separate influences of elevated BMI and diabetes on fetal growth, along with the associated placental mechanisms that influence nutrient transport and fetal growth in pregnancies complicated by obesity and diabetes. UMMC Department of OBGYN. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

IGF-1 infusion increases growth in fetal sheep when euinsulinemia is maintained.

Insulin-like growth factor 1 (IGF-1) is a critical fetal anabolic hormone. IGF-1 infusion to the normally growing sheep fetus increases the weight of some organs but does not consistently increase body weight. However, IGF-1 infusion profoundly decreases fetal plasma insulin concentrations, which may limit fetal growth potential. In this study, normally growing late-gestation fetal sheep received an intravenous infusion of either: IGF-1 (IGF), IGF-1 with insulin and dextrose to maintain fetal euinsulinemia and euglycemia (IGF+INS), or vehicle control (CON) for 1 week. The fetus underwent a metabolic study immediately prior to infusion start and after 1 week of the infusion to measure uterine and umbilical uptake rates of nutrients and oxygen. IGF+INS fetuses were 23% heavier than CON (P = 0.0081) and had heavier heart, liver, and adrenal glands than IGF and CON (P < 0.01). By design, final fetal insulin concentrations in IGF were 62% and 65% lower than IGF+INS and CON, respectively. Final glucose concentrations were similar in all groups. IGF+INS had lower final oxygen content than IGF and CON (P < 0.0001) and lower final amino acid concentrations than CON (P = 0.0002). Final umbilical oxygen uptake was higher in IGF+INS compared to IGF and CON (P < 0.05). Final umbilical uptake of several essential amino acids was higher in IGF+INS compared to CON (P < 0.05). In summary, maintaining euinsulinemia and euglycemia during fetal IGF-1 infusion is necessary to maximally support body growth. We speculate that IGF-1 and insulin stimulate placental nutrient transport to support fetal growth.

Increasing the Understanding of Nutrient Transport Capacity of the Ovine Placentome.

Placental nutrient transport capacity influences fetal growth and development; however, it is affected by environmental factors, which are poorly understood. The objective of this study was to understand the impact of the ovine placentome morphological subtype, tissue type, and maternal parenteral supplementation of arginine mono-hydrochloride (Arg) on nutrient transport capacity using a gene expression approach. Placentomal tissues of types A, B, and C morphologic placentome subtypes were derived from 20 twin-bearing ewes, which were infused thrice daily with Arg (n = 9) or saline (Ctrl, n = 11) from 100 to 140 days of gestation. Samples were collected at day 140 of gestation. Expression of 31 genes involved in placental nutrient transport and function was investigated. Differential expression of specific amino acid transporter genes was found in the subtypes, suggesting a potential adaptive response to increase the transport capacity. Placentomal tissues differed in gene expression, highlighting differential transport capacity. Supplementation with Arg was associated with differential expressions of genes involved in amino acid transport and angiogenesis, suggesting a greater nutrient transport capacity. Collectively, these results indicate that the morphological subtype, tissue type, and maternal Arg supplementation can influence placental gene expression, which may be an adaptive response to alter the transport capacity to support fetal growth in sheep.

Epigenetic modifications of placenta in women with gestational diabetes mellitus and their offspring.

Gestational diabetes mellitus (GDM) is a pregnancy-related complication characterized by abnormal glucose metabolism in pregnant women and has an important impact on fetal development. As a bridge between the mother and the fetus, the placenta has nutrient transport functions, endocrine functions, etc., and can regulate placental nutrient transport and fetal growth and development according to maternal metabolic status. Only by means of placental transmission can changes in maternal hyperglycemia affect the fetus. There are many reports on the placental pathophysiological changes associated with GDM, the impacts of GDM on the growth and development of offspring, and the prevalence of GDM in offspring after birth. Placental epigenetic changes in GDM are involved in the programming of fetal development and are involved in the pathogenesis of later chronic diseases. This paper summarizes the effects of changes in placental nutrient transport function and hormone secretion levels due to maternal hyperglycemia and hyperinsulinemia on the development of offspring as well as the participation of changes in placental epigenetic modifications due to maternal hyperglycemia in intrauterine fetal programming to promote a comprehensive understanding of the impacts of placental epigenetic modifications on the development of offspring from patients with GDM.

9 Randel Lecture: In Vivo investigation of pregnancy Physiology

Abstract Pregnancy in any mammal requires the integration of three distinct compartments; the maternal, placental and fetal compartments. Compromised function of any of the three compartments can result in suboptimal pregnancy outcomes, including increased morbidity and mortality at delivery, reduced livestock production efficiency and adult-onset of metabolically-related disease in humans. To accurately understand the progression of both normal and compromised pregnancies, therefore, requires the simultaneous assessment of all three compartments, which for most species is not technically feasible. Consequently, over the past 60 yr the pregnant sheep has been used extensively for in vivo investigation of pregnancy physiology. The ability to place indwelling catheters, within both maternal and fetal vessels, allows the simultaneous steady-state assessment of uterine and umbilical blood flows, hormone secretion, and nutrient uptake and utilization of nutrients by each of the three compartments, under non-stressed and non-anesthetized conditions. This has provided unrivalled insight into the physiology of pregnancy, and the realization that the placenta is a highly metabolic tissue, utilizing the majority of oxygen and glucose taken up by the uterus. However, the deficit in studying pregnant sheep is the lack of genetic models, readily available in rodents, that could help define specific gene function during pregnancy. Consequently, we developed in vivo lentiviral-mediated RNA interference (RNAi) methods to specifically alter the abundance of specific gene transcripts/proteins within the placenta, beginning at 9 d of gestation (dGA). Our lentiviral-mediated approach limits the RNAi to the trophectoderm derivatives of the placenta. Initially we used this approach to determine the importance of PRR15 and LIN28 during the establishment of pregnancies, but turned our efforts towards combining in vivo RNAi with steady-state physiological assessments during late gestation to examine the function of genes involved in placental nutrient transport (SLC2A3) and placenta derived hormones (CSH). By creating a placental deficiency in SLC2A3, not only was the fetus smaller and hypoglycemic at mid-gestation, but by interfering with placental glucose uptake, maternal hormone concentrations were also impacted, yet near-term, a distinctly different phenotype was present. For the placental hormone CSH (a.k.a. placental lactogen), CSH RNAi not only impacts placental and fetal growth, but also reductions in uterine blood flow, nutrient fluxes to the fetus, and produces an altered hormonal environment. Combining these methodological approaches provides new and often unexpected insights into the physiological integration of the maternal, placental and fetal compartments. Supported by NIH-NICHD grants HD093701 and HD094952.