Over 60% of American women now enter pregnancy either overweight or obese, which increases the risk for the infant to develop obesity, diabetes and cardiovascular disease in childhood and later in life. However, the mechanisms linking the in utero environment in maternal obesity to programming of the fetus for later disease remain poorly understood, which constitutes a major roadblock for the development of specific intervention strategies. Circulating levels of adiponectin are decreased in obese pregnant women and in our mouse model of maternal obesity. We have previously reported that adiponectin, in contrast to its well-known insulin- sensitizing effects in skeletal muscle and liver, inhibits placental insulin and mTOR signaling and amino acid transport. This effect is mediated by activation of trophoblast PPAR??signaling, which increases ceramide synthesis resulting in inhibition of IRS-1. Remarkably, in our novel model of maternal obesity, which shows extensive similarities with the human condition (elevated levels of maternal leptin, glucose intolerance, activation of placental insulin and mTOR signaling, increased placental nutrient transport and fetal overgrowth), restoration of normal circulating levels of adiponectin completely prevented placental dysfunction, fetal hyperglycemia and overgrowth. Our findings demonstrate that low circulating adiponectin in maternal obesity is mechanistically linked to increased placental nutrient transport and fetal growth. However, whether normalization of maternal adiponectin levels in pregnancy attenuates the long-term adverse metabolic and cardiovascular consequences of intrauterine exposure to maternal obesity in the offspring is unknown. Our central hypothesis is that adiponectin supplementation in late pregnancy prevents the development of metabolic and cardiovascular disease in the offspring in response to maternal obesity and that this effect is mediated by adiponectin receptor 2 (AdipoR2) in the placenta. This hypothesis is supported by compelling preliminary data including the demonstration that 3-month old male offspring of obese dams (1) develop obesity, glucose intolerance, hypertriglyceridemia and fatty liver; (2) have up-regulation of fetal cardiac genes, activation of cardiac insulin and mTOR signaling and left ventricular diastolic dysfunction and (3) these developmentally programmed changes are prevented by maternal adiponectin supplementation in pregnancy. Using mini-osmotic pumps, we will supplement adiponectin the last four days of pregnancy to lean and obese dams, with or without trophoblast-specific knock down of AdipoR2, and study male and female offspring at 3 and 6 months of age to address our hypothesis in three specific aims: Determine the effect of adiponectin supplementation in obese dams on offspring metabolism (Aim 1) and cardiovascular function (Aim 2) and to determine the mechanistic role of placental adiponectin receptors in fetal programming in maternal obesity (Aim 3). This work will have a significant and sustained impact on the field because it will lead to a better understanding of the mechanistic role of the placenta in mediating in utero programming and may lead to novel specific intervention strategies to alleviate the adverse effects of maternal obesity on the offspring.

Public Health Relevance

Almost 2/3 of all American pregnant women are overweight or obese, which increases the risk for the infant to develop obesity, diabetes and cardiovascular disease later in life. The mechanisms linking maternal obesity to offspring disease are not well established and no effective treatment to prevent these long-term adverse consequences of obesity in pregnancy is available. In this project we will use an animal model to test whether treating obese dams with adiponectin, a hormone produced by fat tissue, prevents the development of adult disease by modulating placental function. This work is highly relevant for public health because it may lead to novel treatments in pregnancy that will contribute to lessen the burden of chronic disease in children and adults.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Ilekis, John V
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University of Colorado Denver
Obstetrics & Gynecology
Schools of Medicine
United States
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Castillo-Castrejon, Marisol; Powell, Theresa L (2017) Placental Nutrient Transport in Gestational Diabetic Pregnancies. Front Endocrinol (Lausanne) 8:306
Howell, Kristy R; Powell, Theresa L (2017) Effects of maternal obesity on placental function and fetal development. Reproduction 153:R97-R108
Jansson, Thomas (2016) Placenta plays a critical role in maternal-fetal resource allocation. Proc Natl Acad Sci U S A 113:11066-11068
Dimasuay, Kris Genelyn; Boeuf, Philippe; Powell, Theresa L et al. (2016) Placental Responses to Changes in the Maternal Environment Determine Fetal Growth. Front Physiol 7:12
Aye, Irving L M H; Rosario, Fredrick J; Powell, Theresa L et al. (2015) Adiponectin supplementation in pregnant mice prevents the adverse effects of maternal obesity on placental function and fetal growth. Proc Natl Acad Sci U S A 112:12858-63
Díaz, Paula; Powell, Theresa L; Jansson, Thomas (2014) The role of placental nutrient sensing in maternal-fetal resource allocation. Biol Reprod 91:82
Aye, Irving L M H; Gao, Xiaoli; Weintraub, Susan T et al. (2014) Adiponectin inhibits insulin function in primary trophoblasts by PPAR?-mediated ceramide synthesis. Mol Endocrinol 28:512-24
Aye, I L M H; Powell, T L; Jansson, T (2013) Review: Adiponectin--the missing link between maternal adiposity, placental transport and fetal growth? Placenta 34 Suppl:S40-5
Jansson, Thomas; Powell, Theresa L (2013) Role of placental nutrient sensing in developmental programming. Clin Obstet Gynecol 56:591-601
Gaccioli, F; Lager, S; Powell, T L et al. (2013) Placental transport in response to altered maternal nutrition. J Dev Orig Health Dis 4:101-15

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