High adiposity at birth is associated with poor metabolic outcomes and increased risk of obesity in childhood and adult life. Maternal obesity (body mass index >30 kg/m2) is associated with increased fetal adiposity, but not all obese women have obese babies. Maternal insulin sensitivity is a key predictor of fetal fat accrual, but the mechanisms regulating insulin signaling during pregnancy are unknown. We have found that maternal insulin sensitivity improves 120% following delivery of the placenta, suggesting a placental factor may regulate insulin signaling during pregnancy. As placental growth and gene expression is sensitive to maternal insulin levels in early pregnancy, and correlated to adiposity at birth, we propose that maternal-placental crosstalk is key to fetal growth regulation. Placental-derived microRNAs (miRNA) regulate post-transcriptional gene expression in maternal tissues, and are detectable in maternal plasma throughout pregnancy. Thus, miRNAs may provide both a mechanism for maternal-placental crosstalk, and novel indicators of women at risk of high fetal fat accretion. The overall goal of this study is to utilize two well-phenotyped, racially-diverse birth cohorts to identify placental miRNA expression profiles associated with alterations in maternal insulin resistance throughout pregnancy resulting in high neonatal adiposity. We hypothesize that placentas of high adiposity infants have a distinctive miRNA expression profile affecting maternal insulin signaling, resulting in high maternal insulin resistance. To test this hypothesis, we will utilize pre-collected samples from two birth cohorts. The first cohort will consist of four groups: lean and obese women who delivered high or low adiposity offspring. These women all had healthy pregnancies, were not diabetic, and recruited at time of scheduled cesarean section where maternal blood, insulin sensitivity data and placental tissue were collected. In a second cohort, maternal blood and insulin sensitivity were measured in early and late pregnancy and placental tissue was collected at term. In both cohorts, neonatal adiposity was measured. The term cohort will be used to identify placental miRNAs associated with high neonatal adiposity, and the longitudinal cohort will be used to validate these miRNA throughout pregnancy. Upon completion of the proposed studies we will have determined: 1) the identity of miRNAs that are associated with high neonatal adiposity in placentas of lean and obese women; 2) the presence of these placenta-derived miRNAs in maternal plasma in early and late pregnancy; 3) the effect of placenta-derived miRNAs on insulin signaling pathways in skeletal muscle in vitro. Identification of markers of altered placental function affecting neonatal adiposity, detectable non-invasively in early pregnancy, will improve our screening for pregnancies at risk of excessive fetal fat accretion and may lead to specific therapies based on the underlying physiology.

Public Health Relevance

High adiposity at birth is associated with increased risk of obesity, diabetes and heart disease later in life. Maternal insulin sensitivity is one of the strongest predictors of her baby's fat mass at birth. The proposed studies will help us understand how the placenta regulates maternal insulin sensitivity throughout pregnancy and how this impacts neonatal growth and fat deposition.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD091735-04
Application #
9873058
Study Section
Special Emphasis Panel (ZHD1)
Program Officer
Weinberg, David H
Project Start
2017-03-10
Project End
2021-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
079532263
City
Boston
State
MA
Country
United States
Zip Code
02111