Placental Function and the Development of Fetal Overgrowth and Fetal Growth Restriction

Dumolt, Jerad H.; Powell, Theresa L.; Jansson, Thomas

doi:10.1016/j.ogc.2021.02.001

Cited by 52 publications

(39 citation statements)

References 127 publications

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“…Also, in GDM pregnancies, IGF-1 plays a crucial role in glucose homeostasis. Experimental and clinical studies have shown that placental insulin/IGF-1 pathway is promoted in GDM, as with energy-dense diets, increasing the activation of several downstream molecules, particularly mammalian target of rapamycin complex 1 (mTORC1), that augments nutrient transport across the placenta (73,74) and regulates mitochondrial biogenesis and function (75,76). In this way, mTORC1 activation could lead to fetal overgrowth, as it is positively correlated to birth weight (77)(78)(79)(80).…”

Section: Role Of the Insulin/igf Axis In Gdmmentioning

confidence: 99%

“…In this way, mTORC1 activation could lead to fetal overgrowth, as it is positively correlated to birth weight ( 77 – 80 ). This mTORC1 activation could be a result of low circulating levels of adiponectin observed in the mother, a hormone that regulates glucose levels by inhibiting insulin/IGF-1 signaling pathway ( 76 , 81 ) ( Figure 1 ). In this sense, an inverse correlation between free IGF-1 and the risk of developing GDM has been found ( 13 , 72 ).…”

Section: Role Of the Insulin/igf Axis In Gdmmentioning

confidence: 99%

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Gestational Diabetes Mellitus and Energy-Dense Diet: What Is the Role of the Insulin/IGF Axis?

Martín-Estal

Castorena‐Torres

2022

Front. Endocrinol.

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Gestational diabetes mellitus (GDM), is one of the most important pregnancy complications affecting approximately 15% of pregnant women. It is related to several gestational adverse outcomes in the fetus, e.g., macrosomia, shoulder dystocia, stillbirth, neonatal hypoglycemia, and respiratory distress. Women with GDM have a high risk of developing type 2 diabetes in the future. The pathogenesis of GDM is not completely understood; nevertheless, two factors could contribute to its development: β-cell dysfunction and failure in insulin secretion in response to insulin resistance induced by gestation. Both processes, together with the physiological activities of the insulin-like growth factors (IGFs), play a crucial role in glucose transport to the fetus and hence, fetal growth and development. IGFs (both IGF-1 and IGF-2) and their binding proteins (IGFBPs) regulate glucose metabolism and insulin sensitivity. Maternal nutritional status determines the health of the newborn, as it has substantial effects on fetal growth and development. Maternal obesity and an energy-dense diet can cause an increase in insulin and IGF-1 serum levels, producing metabolic disorders, such as insulin resistance, GDM, and high birth weight (> 4,000 g) due to a higher level of body fat. In this way, in GDM pregnancies there is an increase in IGF-1 and IGF-2 serum levels, and a decrease in IGFBP-1 and 4 serum levels, suggesting the crucial role of the insulin/IGF system in this gestational outcome. Here, the present review tries to elucidate the role that energy-dense diets and the insulin/IGF-1 signaling pathway perform in GDM pregnancies.

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Section: Role Of the Insulin/igf Axis In Gdmmentioning

confidence: 99%

Section: Role Of the Insulin/igf Axis In Gdmmentioning

confidence: 99%

Gestational Diabetes Mellitus and Energy-Dense Diet: What Is the Role of the Insulin/IGF Axis?

Martín-Estal

Castorena‐Torres

2022

Front. Endocrinol.

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“…In the placenta, amino acid transport is predominantly supported by the system A and L transporters [15]. System A transporters include Slc38A1 and Slc38A2, which are sodium-dependent [40].…”

Section: Discussionmentioning

confidence: 99%

Nanoparticle-mediated transgene expression of insulin-like growth factor 1 in the growth restricted guinea pig placenta increases placenta nutrient transporter expression and fetal glucose concentrations

Wilson

Stephens

Lampe

et al. 2021

Preprint

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Fetal growth restriction (FGR) occurs in up to 10% of pregnancies and is a leading cause of infant morbidity and mortality. Additionally, FGR has been implicated in contributing to the development of long-term health outcomes including increasing the risk for future cardiovascular and endocrine diseases. Currently, there is limited preventative strategies and no effective treatment options for FGR. To address this need, we are developing a therapeutic targeting the placenta to increase expression of human insulin-like growth factor 1 (hIGF-1) and enhance placental development and function, with the goal of correcting fetal growth trajectories.MethodsInitially, an ultrasound-guided, transcutaneous, intra-placental injection of a non-viral, Texas-red conjugated polymer-based nanoparticle containing a plasmid with the green fluorescent protein (GFP) gene under the control of the placenta-specific promotors Plac1 or Cyp19a1 was performed to determine nanoparticle uptake and transgene expression in the guinea pig placenta. Subsequently, using the established maternal nutrient restriction (MNR) guinea pig model of FGR, placentas were treated with an unconjugated nanoparticle containing a plasmid with the hIGF-1 gene under the Cyp19a1 promotor at mid-pregnancy (gestational day (GD) 30-33). Five days after treatment placentas and fetal liver tissue was collected, weighed, and fixed for histology or snap-frozen for qPCR analysis of mRNA expression.ResultsHistological analysis of Texas-red and GFP fluorescence in placenta and fetal liver tissue confirmed nanoparticle uptake and transgene expression and that nanoparticle was unable to cross the placenta to fetal circulation. In situ hybridization for plasmid-specific mRNA confirmed sustained hIGF-1 expression five days after treatment. MNR resulted in 20-25% decreased fetal weight at mid-pregnancy (P<0.001) that was not changed with nanoparticle treatment (P>0.05). There was no effect of nanoparticle treatment on the volume densities of trophoblasts or fetal capillaries in the placenta (P>0.05 for both). However, treatment did reduce the interhaemal distance between the maternal blood space and fetal circulation in the MNR placentas compared to sham treated MNR placentas (P<0.001). In the fetuses, placental nanoparticle treatment increased circulating glucose by 38-50% (P<0.001) and was associated with differential changes to fetal liver mRNA expression of genes associated with gluconeogenesis. Gene expression changes were dependent on if the fetus was growth restricted or not; nanoparticle treatment: down-regulated gluconeogenesis gene expression in the normal growing fetuses but increased expression in the FGR fetuses.ConclusionsThe current study shows that treatment of the guinea pig placenta with a polymer-based nanoparticle causes expression of hIGF-1 and ultimately increases fetal glucose concentrations within five days of treatment. Furthermore, the data shows that the placenta and fetal liver respond differently to nanoparticle treatment depending on fetal growth conditions.Graphical Abstract

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“…The transplacental flux of nutrients is dependent on the availability and activity of nutrient-specific transporters [5][6][7][8]. Changes in the expression and activity of these transporters are associated with babies born small or large for their gestational age [9]. The placenta mediates the relationship between the maternal nutrient stores and fetal development by controlling nutrient transport and hormone production [2,5].…”

Section: Introductionmentioning

confidence: 99%

Adiponectin Deficiency Alters Placenta Function but Does Not Affect Fetal Growth in Mice

Shrestha

Wermelin

Stener-Victorin

et al. 2022

IJMS

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Adiponectin administration to pregnant mice decreases nutrient transport and fetal growth. An adiponectin deficiency, on the other hand, as seen in obese women during pregnancy, alters fetal growth; however, the mechanism is unclear. To determine the role of adiponectin on placenta function and fetal growth, we used adiponectin knockout, adiponectin heterozygote that displays reduced adiponectin levels, and wild-type mice on a control diet or high fat/high sucrose (HF/HS) diet. Triglycerides (TGs) in the serum, liver, and placenta were measured using colorimetric assays. Gene expression was measured using quantitative RT-PCR. Adiponectin levels did not affect fetal weight, but it reduced adiponectin levels, increased fetal serum and placenta TG content. Wildtype dams on a HF/HS diet protected the fetuses from fatty acid overload as judged by increased liver TGs in dams and normal serum and liver TG levels in fetuses, while low adiponectin was associated with increased fetal liver TGs. Low maternal adiponectin increased the expression of genes involved in fatty acid transport; Lpl and Cd36 in the placenta. Adiponectin deficiency does not affect fetal growth but induces placental dysfunction and increases fetal TG load, which is enhanced with obesity. This could lead to imprinting effects on the fetus and the development of metabolic dysfunction in the offspring.

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Placental Function and the Development of Fetal Overgrowth and Fetal Growth Restriction

Cited by 52 publications

References 127 publications

Gestational Diabetes Mellitus and Energy-Dense Diet: What Is the Role of the Insulin/IGF Axis?

Gestational Diabetes Mellitus and Energy-Dense Diet: What Is the Role of the Insulin/IGF Axis?

Nanoparticle-mediated transgene expression of insulin-like growth factor 1 in the growth restricted guinea pig placenta increases placenta nutrient transporter expression and fetal glucose concentrations

Adiponectin Deficiency Alters Placenta Function but Does Not Affect Fetal Growth in Mice

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