The baby of the obese woman is often large at birth, which is associated with traumatic birth injuries and an increased risk to develop the metabolic syndrome in childhood. There is now a body of evidence to suggest that changes in placental nutrient transporter activity directly contribute to altered fetal growth both in IUGR and in fetal overgrowth in association to maternal diabetes in humans. However, the mechanisms underlying fetal overgrowth in maternal obesity are unknown, and the lack of relevant animal models has severely hampered progress in this area. Our long-term goals are to elucidate the mechanisms regulating placental nutrient transport and to understand the role of altered placental transport functions in abnormal fetal growth. The objective of this R03 application is to develop and establish feasibility of a mouse model of obesity in pregnancy in order to determine the mechanisms underlying fetal overgrowth in response to high fat diet and increased adiposity. The central hypothesis is that feeding female C57BL/6J mice, a strain susceptible to diet induced obesity, a diet with moderately high fat content prior to mating and throughout pregnancy will result in a metabolic profile similar to that of obese pregnant women, up-regulation of placental nutrient transport and fetal overgrowth. The rationale for this R03 proposal is that, once an appropriate model has been validated, it will enable subsequent mechanistic studies at the R01 level. Guided by preliminary data showing a 45% increase in fetal weight in response to high fat diet in our model, the central hypothesis will be tested in two specific aims: (1) Develop a mouse model of obesity in pregnancy that is relevant for the human condition, and (2) Identify the mechanisms underlying fetal overgrowth in obese mice. In both aims, female C57BL/6J mice will be fed either a control diet (11% of calories from fat) or a high fat diet (32 % of calories from fat) from 8 weeks prior to and throughout pregnancy. Animals will be studied at embryonic day 18.
In aim 1, fetal and placental weights will be measured, maternal adiposity will be assessed using fat pad weights and in vivo quantitative magnetic resonance, intravenous glucose tolerance test will be performed and blood samples obtained to characterize animals metabolically (serum concentrations of insulin, leptin, TNF-?, IL-6, and adiponectin).
In aim 2, placental glucose and amino acid transporters (System A and L) will be studied in vivo using isotope labeled substrates. In addition, we will determine the placental gene (real-time PCR) and protein expression (Western blots) of relevant transporter isoforms, i.e., glucose transporter isoforms 1 and 3, System A isoforms SNAT 1, 2 and 4 and L-system amino acid transporter isoforms LAT 1, LAT2 and 4F2hc. This study is innovative because we propose to establish a mouse model of obesity in pregnancy, which results in fetal overgrowth thereby resembling the clinical condition. Currently, no such model is available. The significance of the proposed work is that it will increase our understanding of the mechanisms linking maternal obesity to fetal overgrowth and provide a foundation for the development of novel intervention strategies. More than 50% of pregnant women in the US are overweight or obese and these pregnancies are often complicated by fetal overgrowth, which increases the risk for complications around the time of birth and for developing obesity, diabetes and high blood pressure in childhood. The proposed research is relevant to public health because we expect to establish a unique animal model of obesity in pregnancy that will be used to elucidate the mechanisms underlying fetal overgrowth in maternal obesity. These studies are expected to generate new knowledge that will provide a foundation for the development of novel treatments in order to alleviate fetal overgrowth, which could prevent a number of perinatal complications as well as important diseases in childhood and later in life. ? ? ?
|Jones, Helen N; Woollett, Laura A; Barbour, Nicolette et al. (2009) High-fat diet before and during pregnancy causes marked up-regulation of placental nutrient transport and fetal overgrowth in C57/BL6 mice. FASEB J 23:271-8|