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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（由申请方提供）：令人信服的动物和人类流行病学证据支持母体肥胖和糖尿病形成宫内环境，促进胎儿过度生长，改变出生时的身体组成，并可能增加儿童肥胖的风险。尽管妊娠期糖尿病（GDM）引起的明显高血糖被认为是影响胎儿脂肪堆积的主要原因，但大于胎龄儿（LGA）数量的惊人增加主要是由不符合GDM诊断标准的肥胖妇女所生。作为我们的R56试点补助金的结果，我们证明了孕妇空腹甘油三酯（TG）从妊娠早期到晚期的变化与新生儿肥胖之间的显著相关性（r=0.91; p=0.001），独立于孕妇BMI。这种相关性甚至强于我们在控制饮食期间通过72小时连续葡萄糖监测（CGMS）检测隐性高血糖症的最稳健的血糖指数;（r=0.79; p=0.01）。此外，我们观察到一个完全钝化的餐后TG漂移后，液体餐，尽管一个强大的胰岛素反应和抑制游离脂肪酸（FFA），这表明快速TG清除。我们的R56试点研究结果强调，需要进一步研究FFA的可用性作为一个关键的胎儿燃料，在了解新生儿肥胖的精益和肥胖的孕妇和不GDM，无论是早期和晚期的妊娠。我们还将跟踪婴儿，以评估一岁时肥胖表型的持久性。基于我们的初步数据，我们假设新生儿肥胖是由以下因素预测的：1）由于VLDL-TG可用性增加和母体膳食脂肪摄入量增加，妊娠期间空腹TG增加，2）胎盘LPL活性升高和白色脂肪组织（WAT）LPL活性降低，这增加了胎儿FFA可用性，3）隐匿性高血糖，与GDM状态无关。此外，我们假设我们可以预测新生儿肥胖的胎儿超声三维体积参数的28周妊娠和肥胖表型将持续到一岁，促进婴儿膳食脂肪摄入。在目标1中，我们将研究空腹和餐后状态下TG颗粒的来源。在目标2中，我们将测定母体WAT和胎盘中的LPL活性，以评估这些组织的脂解活性。在目标3中，我们将继续研究在控制饮食期间，符合GDM标准的肥胖妇女与不符合GDM标准的肥胖妇女之间GCMS血糖指数是否存在差异。在目标4中，我们将在多元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，作为一个探索性的目标，我们通过一年的婴儿，并确定是否肥胖表型持续使用DXA和PEAPOD或婴儿膳食脂肪摄入量的影响。我们认为，R 01重新提交的研究结果可能会挑战目前对胎儿脂肪堆积的燃料背后的想法，并最终导致子宫内和婴儿早期安全有效的干预措施，这可能有助于降低儿童肥胖的风险。