More than 60% of American women enter pregnancy overweight or obese and fetal overgrowth is common in these pregnancies. Fetal overgrowth increases the risk for traumatic birth injuries and predisposes the baby for development of obesity, diabetes and hypertension in childhood and later in life. The mechanisms underlying the increased fetal growth in overweight/obese women are largely unknown. Our overall model is that increased levels of pro-inflammatory cytokines, leptin and free fatty acids (FFA) in overweight/obese women cause an increase in TNF- and IL-6 release from the placenta. We propose that these cytokines stimulate amino acid transporter expression and activity, which in vivo will result in increased nutrient delivery to the fetus and ultimately increased fetal growth. To address this model our central hypothesis is that FFA stimulate placental amino acid transport mediated by multiple signaling pathways including binding to Toll Like Receptor 4 resulting in activation of MAP kinase and NF which promotes production of cytokines such as IL-6. We further propose that cytokines, produced by the trophoblast and circulating in maternal plasma, up-regulate trophoblast amino acid transport by affecting transcription, translation and/or membrane trafficking of specific amino acid transporter isoforms, mediated in part by STAT3. We will address this central hypothesis in three specific aims: 1. Determine the impact of high maternal body mass index (BMI) on key intracellular signaling pathways and placental nutrient transport capacity. We will recruit 75 lean, overweight and obese pregnant women and measure expression and activity of key intracellular signaling pathways and nutrient transporters in placenta and correlate these to maternal BMI and metabolic parameters. 2. Establish the effect of FFA on placental cytokine production and define the intracellular signaling pathway mediating the effects. Using primary human trophoblast cells and siRNA techniques, we will delineate the intracellular signaling pathway linking FFA to increased cytokine release. 3. Determine the effect of pro-inflammatory cytokines on placental amino acid transport and identify the intracellular signaling mechanisms involved. The role of key intracellular signaling molecules, such as STAT 3, will be investigated employing siRNA approaches in cultured human primary trophoblast cells, and we will examine three levels of potential regulation of placental amino acid transport capacity: gene transcription, protein translation and membrane trafficking. Our preliminary data give strong support for our central hypothesis. The proposed studies are innovative because they are expected to identify a mechanistic link between the perturbed maternal metabolism in obesity and alterations in placental function, which increases nutrient delivery to the fetus. The significance of this study is that it will provide novel information on the mechanisms underlying fetal overgrowth, which may allow for the development of new intervention strategies in order to reduce fetal overgrowth and its'short- and long-term health consequences.

Public Health Relevance

Overweight and obese women often deliver large babies, which have a high risk to develop obesity, diabetes and hypertension already in childhood. We propose that changes in placental nutrient transport constitutes an important mechanism by which maternal obesity leads to increased birth weight. This is highly relevant to public health since this new information may lead to novel intervention strategies to alleviate fetal overgrowth, which could lessen the epidemic of obesity and diabetes in the next generation.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pregnancy and Neonatology Study Section (PN)
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Silva, Corinne M
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University of Texas Health Science Center San Antonio
Obstetrics & Gynecology
Schools of Medicine
San Antonio
United States
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Howell, Kristy R; Powell, Theresa L (2017) Effects of maternal obesity on placental function and fetal development. Reproduction 153:R97-R108
Cleaton, Mary A M; Dent, Claire L; Howard, Mark et al. (2016) Fetus-derived DLK1 is required for maternal metabolic adaptations to pregnancy and is associated with fetal growth restriction. Nat Genet 48:1473-1480
Lager, Susanne; Ramirez, Vanessa I; Gaccioli, Francesca et al. (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 40:60-6
Pantham, P; Aye, I L M H; Powell, T L (2015) Inflammation in maternal obesity and gestational diabetes mellitus. Placenta 36:709-15
Gaccioli, Francesca; Aye, Irving L M H; Roos, Sara et al. (2015) Expression and functional characterisation of System L amino acid transporters in the human term placenta. Reprod Biol Endocrinol 13:57
Acosta, Ometeotl; Ramirez, Vanessa I; Lager, Susanne et al. (2015) Increased glucose and placental GLUT-1 in large infants of obese nondiabetic mothers. Am J Obstet Gynecol 212:227.e1-7
Aye, Irving L M H; Jansson, Thomas; Powell, Theresa L (2015) TNF-? stimulates System A amino acid transport in primary human trophoblast cells mediated by p38 MAPK signaling. Physiol Rep 3:
Lager, Susanne; Jansson, Thomas; Powell, Theresa L (2014) Reply to ""Letter to the editor: 'fatty acids and placental transport: insight or in vitro artifact?'"". Am J Physiol Cell Physiol 307:C1069
Díaz, Paula; Powell, Theresa L; Jansson, Thomas (2014) The role of placental nutrient sensing in maternal-fetal resource allocation. Biol Reprod 91:82
Lager, S; Ramirez, V I; Gaccioli, F et al. (2014) Expression and localization of the omega-3 fatty acid receptor GPR120 in human term placenta. Placenta 35:523-5

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