Regulation of Maternal Fuel Supply and Neonatal Adiposity

母体燃料供应和新生儿肥胖的调节

基本信息

批准号：
8640927
负责人：
LINDA Anne BARBOUR
金额：
$ 49.62万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-15 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8640927
关键词：
Accounting Adherence Adipose tissue Adolescent Affect Age-Years Animal Model Animals Apolipoproteins B Appearance Biological Markers Birth Birth Weight Body Composition Body Weight Body fat Cell membrane Childhood Data Deposition Development Diabetes Mellitus Diagnosis Diagnostic Diet Dietary Fats Dual-Energy X-Ray Absorptiometry Environment Epidemic Epidemiology Erythrocytes Evolution Fasting Fatty acid glycerol esters Fetus Gestational Age Gestational Diabetes Glucose Glycemic Index Grant Hormones Hour Human Hydrolysis Hyperglycemia Hypertriglyceridemia Infant Inflammation Insulin Insulin Resistance Intake Lead Learning Life Light Limb structure Lipids Lipolysis Lipoproteins Liquid substance Mammals Mass Fragmentography Measures Metabolic Modeling Mothers Neonatal Nonesterified Fatty Acids Obesity Phenotype Placenta Placentation Play Pregnancy Pregnant Women Production Rattus Regulation Relative (related person)Risk Role Serum Source Thigh structure Thinking Tissues Triglycerides Ultrasonography Very low density lipoprotein Woman animal data apolipoprotein B-48 base design effective intervention effective therapy epidemiologic data fasting glucose feeding fetal fetal programming glucose monitor glucose uptake in utero indexing infancy lipid biosynthesis neonate obesity in children particle placental transfer pregnant programs public health relevance response saturated fat treatment strategy very low density lipoprotein triglyceride

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：引人注目的动物和人类流行病学证据支持孕产妇肥胖和糖尿病创造一种促进胎儿过度生长的宫内环境，从而改变了出生时身体成分，并可能会增强儿童肥胖的风险。尽管妊娠糖尿病（GDM）的Frank高血糖症被认为是影响胎儿脂肪吸收的主要燃料来源，但妊娠年龄（LGA）婴儿数量的令人震惊的增加，主要是针对不符合GDM诊断标准的肥胖女性的天生。由于我们的R56飞行员赠款，我们证明了孕产妇禁食甘油三酸酯（TG）从妊娠到晚期到晚期的变化与婴儿DXA（r = 0.91; p = 0.001）测量的新生儿肥胖，独立于母体BMI。这种相关性甚至比我们在受控饮食期间通过72小时连续葡萄糖监测（CGM）进行72小时连续葡萄糖监测（CGM）的最强大血糖指数更强。（r = 0.79; p = 0.01）。此外，尽管有强大的胰岛素反应和抑制游离脂肪酸（FFA），但我们观察到液体粉后餐后完全钝的餐后TG游览（FFA），这表明TG清除率很快。我们的R56试点调查结果强调，需要进一步研究FFA的可用性，以作为了解有或没有GDM的瘦和肥胖孕妇的新生儿肥胖，包括妊娠的早期和晚期。我们还将跟随婴儿评估一年生命一年的肥胖表型的永久性。 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.此外，我们假设我们可以在妊娠28周之前通过胎儿超声3D体积参数来预测新生儿的肥胖，并且由婴儿饮食脂肪摄入促进，肥胖表型将持续到一岁。在AIM 1中，我们将研究禁食和餐后状态下TG颗粒的来源。在AIM 2中，我们将确定母体WAT和胎盘中的LPL活性，以评估这些组织的脂解活性。在AIM 3中，我们将继续调查受控饮食期间GCMS血糖指数在适合GDM标准的肥胖女性与没有的肥胖女性之间是否有所不同。在AIM 4中，我们将在多回归模型中纳入最重要的母体变量，以预测新生儿肥胖。最后，作为探索目的，我们跟随婴儿一年，并确定使用DXA和PEAPOD的肥胖表型是否持续存在，还是受婴儿饮食脂肪摄入的影响。我们认为，我们的R01重新提取的发现可能会挑战负责胎儿脂肪积聚的燃料背后的思想，并最终导致UTERO内和婴儿早期的安全有效干预措施，这可能有助于降低儿童肥胖的风险。