Obesity is the most common medical condition in women of reproductive age. Obesity during pregnancy has short term and long term adverse consequences for both mother and child. Obesity causes problems with infertility, and in early gestation it causes spontaneous pregnancy loss and congenital anomalies. Metabolically, obese women have increased insulin resistance in early pregnancy, which becomes manifest clinically in late gestation as glucose intolerance and fetal overgrowth. At term, the risk of cesarean delivery and wound complications is increased. Postpartum, obese women have an increased risk of venous thromboembolism, depression, and difficulty with breast feeding. Because 50-60% of overweight or obese women gain more than recommended by Institute of Medicine gestational weight guidelines, postpartum weight retention increases future cardiometabolic risks and prepregnancy obesity in subsequent pregnancies. Neonates of obese women have increased body fat at birth, which increases the risk of childhood obesity. Although there is no unifying mechanism responsible for the adverse perinatal outcomes associated with maternal obesity, on the basis of the available data, increased prepregnancy maternal insulin resistance and accompanying hyperinsulinemia, inflammation, and oxidative stress seem to contribute to early placental and fetal dysfunction. We will review the pathophysiology underlying these data and try to shed light on the specific underlying mechanisms.

Obesity and pregnancy: mechanisms of short term and long term adverse consequences for mother and child

Epidemiological evidence links an individual's susceptibility to chronic disease in adult life to events during their intrauterine phase of development. Biologically this should not be unexpected, ...

Placental Origins of Chronic Disease.

Appropriate in utero growth is essential for offspring development and is a critical contributor to long-term health. Fetal growth is largely dictated by the availability of nutrients in maternal circulation and the ability of these nutrients to be transported into fetal circulation via the placenta. Substrate flux across placental gradients is dependent on the accessibility and activity of nutrient-specific transporters. Changes in the expression and activity of these transporters is implicated in cases of restricted and excessive fetal growth, and may represent a control mechanism by which fetal growth rate attempts to match availability of nutrients in maternal circulation. This review provides an overview of placenta nutrient transport with an emphasis on macro-nutrient transporters. It highlights the changes in expression and activity of these transporters associated with common pregnancy pathologies, including intrauterine growth restriction, macrosomia, diabetes and obesity, as well as the potential impact of maternal diet. Molecular signaling pathways linking maternal nutrient availability and placenta nutrient transport are discussed. How sexual dimorphism affects fetal growth strategies and the placenta’s response to an altered intrauterine environment is considered. Further knowledge in this area may be the first step in the development of targeted interventions to help optimize fetal growth.

https://www.mdpi.com/1422-0067/15/9/16153/pdf

Maternal-fetal nutrient transport in pregnancy pathologies: the role of the placenta.

Context: Babies of obese women are often large at birth, which is associated with perinatal complications and metabolic syndrome later in life. The mechanisms linking maternal obesity to fetal overgrowth are largely unknown. Objective: We tested the hypothesis that placental insulin/IGF-I and mammalian target of rapamycin (mTOR) signaling is activated and amino acid transporter activity is increased in large babies of obese women. Design and Setting: Pregnant women were recruited prospectively for collection of placental tissue at a university hospital and academic biomedical center. Patients or Other Participants: Twenty-three Swedish pregnant women with first trimester body mass index ranging from 18.5 to 44.9 kg/m2 and with uncomplicated pregnancies participated in the study. Interventions: There were no interventions. Main Outcome Measures: We determined the phosphorylation of key signaling molecules (including Akt, IRS-1, S6K1, 4EBP-1, RPS6, and AMPK) in the placental insulin/IGF-I, AMPK, and mTOR si...

/pdf/activation-of-placental-mtor-signaling-and-amino-acid-4fqb1x37f0.pdf

Activation of Placental mTOR Signaling and Amino Acid Transporters in Obese Women Giving Birth to Large Babies

Maternal obesity is associated with a lipotoxic placental environment.

Knowledge of the consequences of maternal obesity in human placental fatty acids (FA) transport and metabolism is limited. Animal studies suggest that placental uptake of maternal FA is altered by maternal overnutrition. We hypothesized that high maternal body mass index (BMI) affects human placental FA transport by modifying expression of key transporters. Full-term placentas were obtained by vaginal delivery from normal weight (BMI, 18.5-24.9 kg/m(2)) and obese (BMI > 30 kg/m(2)) women. Blood samples were collected from the mother at each trimester and from cord blood at delivery. mRNA and protein expression levels were evaluated with real-time RT-PCR and Western blotting. Lipoprotein lipase (LPL) activity was evaluated using enzyme fluorescence. In vitro linoleic acid transport was studied with isolated trophoblasts. Our results demonstrated that maternal obesity is associated with increased placental weight, decreased gestational age, decreased maternal high-density lipoprotein (HDL) levels during the first and third trimesters, increased maternal triglyceride levels during the second and third trimesters, and increased maternal T3 levels during all trimesters, and decreased maternal cholesterol (CHOL) and low-density lipoprotein (LDL) levels during the third trimester; and increased newborn CHOL, LDL, apolipoprotein B100, and T3 levels. Increases in placental CD36 mRNA and protein expression levels, decreased SLC27A4 and FABP1 mRNA and protein and FABP3 protein expression, and increased LPL activity and decreased villus cytotrophoblast linoleic acid transport were also observed. No changes were seen in expression of PPARA, PPARD, or PPARG mRNA and protein. Overall this study demonstrated that maternal obesity impacts placental FA uptake without affecting fetal growth. These changes, however, could modify the fetus metabolism and its predisposition to develop diseases later in life.

https://bioone.org/journals/biology-of-reproduction/volume-87/issue-1/biolreprod.111.098095/Modulation-of-Fatty-Acid-Transport-and-Metabolism-by-Maternal-Obesity/10.1095/biolreprod.111.098095.pdf

Modulation of fatty acid transport and metabolism by maternal obesity in the human full-term placenta.

Gestational diabetes mellitus (GDM) is a common complication of pregnancy that is characterized by glucose intolerance, leads to dyslipidemia, and is aggravated by obesity. Cholesterol is taken up by the placenta as part of lipoproteins through the scavenger receptor class B type I receptor (SRBI), low-density lipoprotein receptor (LDLR), and very low density lipoprotein receptor (VLDLR), and its efflux is then mediated by ABCA1 and ABCG1. PCSK9 is involved in the degradation of LDLR and VLDLR. The goal of this study was to evaluate the impact of GDM and prepregnancy body mass index (BMI) on cholesterol transport through the modulation of the expression of several key players. Human full-term placenta, maternal, and venous cord blood samples were obtained at delivery from normal-weight women without GDM (n = 10), normal-weight women with GDM (n = 6), and overweight/obese women with GDM (n = 6). Lipids (total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, free fatty acids, apolipoprotein A1, apolipoprotein B100) levels were evaluated in blood samples. Messenger RNA and protein expression levels (LDLR, VLDLR, SRBI, ABCA1, ABCG1, proprotein convertase subtilisin/kexin type 9, liver x receptors, peroxisome proliferator-activated receptors) were assessed in human full-term placenta, respectively, by real-time RT-PCR and Western blots. Lipoprotein lipase activity was evaluated using a commercial kit on tissue homogenates. Overall, our study demonstrates that GDM affects the maternal and neonatal lipid profiles as well as different key players of placental cholesterol transfer from the maternal to the fetal circulation, depending on the maternal BMI. These changes could affect the fetal metabolism and predispose the fetus to future metabolic diseases.

https://bioone.org/journals/biology-of-reproduction/volume-88/issue-1/biolreprod.112.105619/Modulation-of-Cholesterol-Transport-by-Insulin-Treated-Gestational-Diabetes-Mellitus/10.1095/biolreprod.112.105619.pdf

Modulation of Cholesterol Transport by Insulin-Treated Gestational Diabetes Mellitus in Human Full-Term Placenta

Embryo implantation is a complex process; primary step in implantation is the initiation of dialogue between free floating blastocyst and the receptive endometrium. This is followed by a stable adhesion of the blastocyst anchors to the endometrial basal lamina and stromal extracellular matrix. The last step is invasion of the embryo through the luminal epithelium and its basal lamina into the uterine stroma. Successful embryo implantation depends up on number of factors like steroid hormones (progesterone, estrogen), Cyclooxygenases, prostaglandins, cytokines, growth factors, transcription factors (HOXA-10 and HOXA-11), and adhesion molecules (integrins, selectins, cadherins, mucins) and receptive endometrium. Importantly, there is timely regulation of these factors and their cross talk which mediates the implantation process. Blastocyst is unable to implant successfully if there is deregulation in any of these factors leading to pregnancy loss. In this chapter we reviewed the information available till date to provide possible causes of implantation failure and its positive outcomes.

Pregnancy Disorders and Perinatal Outcomes

The human placenta is responsible for the adequate supply of nutrients essential for proper embryonic and fetal development such as glucose, amino acids, and lipids. Processes involved in the placental transport of these nutrients are complex and tightly regulated and involve many transporters, receptors, and regulators. In this chapter, we describe the current methods to study the impact of maternal metabolic disorders on key players of human placental transfer of nutrients.

Evemie Dubé

Papers

Modulation of fatty acid transport and metabolism by maternal obesity in the human full-term placenta.

Modulation of Cholesterol Transport by Insulin-Treated Gestational Diabetes Mellitus in Human Full-Term Placenta

Pregnancy Disorders and Perinatal Outcomes

Placental Lipid Transport.

Gestational Diabetes Affects Placental-Fetal Development