Mounting epidemiological evidence suggests that maternal obesity and Gestational Diabetes Mellitus (GDM) independently influence size at birth and disease susceptibility later in life. A major gap in our understanding of fetal programming is knowledge of whether and how exposure to excess maternal fuels in the absence of frank hyperglycemia impacts fetal fat accretion. Our hypothesis is that neonatal adiposity and insulin resistance result from unrecognized maternal hyperglycemia and excess lipid availability in pregnancy, in part due to an earlier switch from adipogenesis to lipolysis in obese women.
In Aim 1 we will utilize stable isotope technology to determine maternal glycerol turnover in the fasted and insulin suppressed state, a liquid meal to assess postprandial TG excursions, respiratory gas exchange to measure lipid and carbohydrate oxidation, DXA to determine body composition, and continuous glucose monitoring both early and late in pregnancy in lean, obese, and GDM subjects.
In Aim 2, we will test the hypothesis that neonatal adiposity determined by DXA are strongly correlated with excess lipid and glucose availability in obese mothers with and without GDM who manifest both of these abnormalities early in gestation. Furthermore, we will test the hypothesis that neonatal insulin sensitivity, as assessed by oral glucose tolerance tests and cardiovascular risk markers, can at least be partially predicted by fetal and/or neonatal adiposity.
In Aim 3 we will relate changes in total body lipolysis to molecular differences in maternal adipose tissue between lean and obese pregnant women. Evidence from our laboratories indicates that human placental growth hormone leads to a functional inhibition of two molecules, PPARg and adiponectin, whose activities are required for the maintenance of insulin sensitivity. We predict that in obese women this switch to insulin resistance is earlier or more profound, thereby accelerating lipolysis making excess FFA and glucose more readily available to the fetal-placental unit. We will contrast the differences in markers of adipocyte differentiation/function including cell size distribution, adiponectin secretion, and insulin signaling and suppression of lipolysis in adipocytes from lean, obese and GDM women obtained in early and late pregnancy. The elucidation of specific derangements in both glucose and lipid metabolism and their timing in gestation in mothers who deliver infants with excess adiposity could challenge our current screening methods and entirely redirect our treatment to target the responsible maternal fuels. On a public health level, this research is instrumental to our understanding of how an intrauterine environment may deliver excess glucose and/or lipids to the fetus and contribute to the genesis of the pediatric obesity epidemic. Such information may result in new treatment strategies in pregnant women to normalize fetal growth.
| Barbour, Linda A; Hernandez, Teri L (2018) Maternal Non-glycemic Contributors to Fetal Growth in Obesity and Gestational Diabetes: Spotlight on Lipids. Curr Diab Rep 18:37 |
| Barbour, Linda A; Farabi, Sarah S; Friedman, Jacob E et al. (2018) Postprandial Triglycerides Predict Newborn Fat More Strongly than Glucose in Women with Obesity in Early Pregnancy. Obesity (Silver Spring) 26:1347-1356 |
| Barbour, L A; Hernandez, T L; Reynolds, R M et al. (2016) Striking differences in estimates of infant adiposity by new and old DXA software, PEAPOD and skin-folds at 2 weeks and 1 year of life. Pediatr Obes 11:264-71 |
| Brumbaugh, David E; Friedman, Jacob E (2014) Developmental origins of nonalcoholic fatty liver disease. Pediatr Res 75:140-7 |
