Compelling animal and human epidemiologic evidence supports that maternal obesity and diabetes create an intrauterine environment promoting fetal overgrowth which alters body composition at birth and may potentiate the risk of childhood obesity. Although frank hyperglycemia from gestational diabetes (GDM) is recognized as a major fuel source affecting fetal fat accretion, the alarming increase in the number of large for gestational age (LGA) infants are being born primarily to obese women who do not fit diagnostic criteria for GDM. As a result of our R56 pilot grant, we demonstrated a remarkably strong correlation between the change in maternal fasting triglycerides (TG) from early to late gestation and neonatal adiposity as measured by infant DXA (r=0.91;p=0.001), independent of maternal BMI. This correlation is even stronger than our most robust glycemic indices used to detect occult hyperglycemia by 72 hr continuous glucose monitoring (CGMS) during a controlled diet;(r=0.79;p=0.01). Furthermore, we observed a completely blunted postprandial TG excursion after a liquid meal despite a robust insulin response and suppression of free fatty acids (FFA), suggesting rapid TG clearance. Our R56 pilot findings highlight the need to further investigate FFA availability as a key fetal fuel in understanding neonatal adiposity in lean and obese pregnant women with and without GDM, both early and late in gestation. We will also follow the infants to assess the permanence of the adiposity phenotype at one year of life. We hypothesize, based on our pilot data, that neonatal adiposity is predicted by 1) increases in fasting TG over gestation as a result of increased VLDL-TG availability and higher maternal dietary fat intake, 2) higher placental LPL activity and reduced white adipose tissue (WAT) LPL activity which augments fetal FFA availability, and 3) occult hyperglycemia independent of GDM status. Further, we hypothesize we can predict neonatal adiposity by fetal ultrasound 3D volume parameters by 28 weeks gestation and that the adiposity phenotype will persist through one year of age, promoted by infant dietary fat intake.
In Aim 1 we will investigate the source of TG particles both in the fasting and postprandial state.
In Aim 2 we will determine LPL activity in maternal WAT and the placenta to assess the lipolytic activities of these tissues.
In Aim 3 we will continue to investigate whether GCMS glycemic indices during a controlled diet differ between obese women who fit criteria for GDM versus those who do not.
In aim 4 we will incorporate the most significant maternal variables in a multiple regression model in order to predict neonatal adiposity. Lastly, as an exploratory aim, we follow the infants through one year and determine whether the adiposity phenotype persists using DXA and PEAPOD or is influenced by infant dietary fat intake. We believe that the findings in our R01 resubmission may challenge the current thinking behind the fuels responsible for fetal fat accretion and ultimately lead to safe and effective interventions in-utero and in early infancy which may help to decrease the risk of childhood obesity.
The number of infants who are born large for gestational age and who are at risk for childhood obesity has risen dramatically in recent years. Thus, it is important to learn how the intrauterine environment may deliver excess lipids and glucose to the fetus in obese pregnant women who may not fit current criteria for gestational diabetes. The metabolic and dietary information obtained during pregnancy and throughout the first year of life from these studies may lead to new treatment strategies, both in pregnancy and in early infancy, that may ultimately help to mitigate the childhood obesity epidemic.
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|Dutton, Heidi; Borengasser, Sarah Jean; Gaudet, Laura Marie et al. (2018) Obesity in Pregnancy: Optimizing Outcomes for Mom and Baby. Med Clin North Am 102:87-106|
|Barbour, Linda A; Hernandez, Teri L (2018) Maternal Lipids and Fetal Overgrowth: Making Fat from Fat. Clin Ther 40:1638-1647|
|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|
|Heerwagen, Margaret J R; Gumina, Diane L; Hernandez, Teri L et al. (2018) Placental lipoprotein lipase activity is positively associated with newborn adiposity. Placenta 64:53-60|
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|Nicklas, Jacinda M; Barbour, Linda A (2015) Optimizing Weight for Maternal and Infant Health - Tenable, or Too Late? Expert Rev Endocrinol Metab 10:227-242|
|Friedman, Jacob E (2015) Obesity and Gestational Diabetes Mellitus Pathways for Programming in Mouse, Monkey, and Man—Where Do We Go Next? The 2014 Norbert Freinkel Award Lecture. Diabetes Care 38:1402-11|
|Boyle, Kristen E; Hwang, Hyonson; Janssen, Rachel C et al. (2014) Gestational diabetes is characterized by reduced mitochondrial protein expression and altered calcium signaling proteins in skeletal muscle. PLoS One 9:e106872|
|Brumbaugh, David E; Friedman, Jacob E (2014) Developmental origins of nonalcoholic fatty liver disease. Pediatr Res 75:140-7|
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