Regulation of Maternal Fuel Supply and Neonatal Adiposity

母体燃料供应和新生儿肥胖的调节

• 批准号: 8230699
• 负责人: LINDA Anne BARBOUR
• 金额: $ 50.25万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230699
• 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

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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：令人信服的动物和人类流行病学证据表明，母亲肥胖和糖尿病会产生促进胎儿过度生长的宫内环境，从而改变出生时的身体成分，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燃料来源，但大于胎龄（LGA）婴儿数量的惊人增加主要是由不符合诊断标准的肥胖妇女所出生的。 GDM。由于我们的 R56 试点资助，我们证明了从妊娠早期到妊娠晚期的母亲空腹甘油三酯 (TG) 变化与婴儿 DXA 测量的新生儿肥胖之间存在非常强的相关性 (r=0.91；p=0.001)，独立于母亲体重指数。这种相关性甚至比我们最强大的血糖指数更强，该指数用于在控制饮食期间通过 72 小时连续血糖监测 (CGMS) 来检测隐匿性高血糖； （r=0.79；p=0.01）。此外，我们观察到，尽管胰岛素反应强劲且游离脂肪酸 (FFA) 受到抑制，但流质餐后餐后 TG 偏移完全减弱，这表明 TG 清除速度很快。我们的 R56 试点研究结果强调需要进一步调查 FFA 的可用性，作为了解妊娠早期和晚期瘦和肥胖孕妇（无论是否患有 GDM）的新生儿肥胖的关键胎儿燃料。我们还将跟踪婴儿，评估婴儿一岁时肥胖表型的持久性。根据我们的试点数据，我们假设新生儿肥胖的预测因素为：1) 由于 VLDL-TG 可用性增加和母亲膳食脂肪摄入量增加，妊娠期空腹 TG 增加；2) 胎盘 LPL 活性增加和白色脂肪组织减少(WAT) LPL 活性可增加胎儿 FFA 的可用性，3) 与 GDM 状态无关的隐匿性高血糖。此外，我们假设我们可以在妊娠 28 周时通过胎儿超声 3D 体积参数来预测新生儿肥胖，并且肥胖表型将持续到一岁，这是由婴儿膳食脂肪摄入所促进的。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肪分解活性。在目标 3 中，我们将继续研究在控制饮食期间，符合 GDM 标准的肥胖女性与不符合 GDM 标准的肥胖女性之间的 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亲变量，以预测新生儿肥胖。最后，作为探索性目标，我们跟踪婴儿一年，并确定使用 DXA 和 PEAPOD 的肥胖表型是否持续存在，或者是否受到婴儿饮食脂肪摄入的影响。我们相信，我们重新提交的 R01 中的发现可能会挑战目前对导致胎儿脂肪堆积的燃料背后的想法，并最终导致在子宫内和婴儿早期采取安全有效的干预措施，这可能有助于降低儿童肥胖的风险。 公共卫生相关性：近年来，出生时大于胎龄且有儿童肥胖风险的婴儿数量急剧增加。因此，了解子宫内环境如何向可能不符合当前妊娠糖尿病标准的肥胖孕妇的胎儿输送过量的脂质和葡萄糖非常重要。从这些研究中获得的怀孕期间和生命第一年的代谢和饮食信息可能会导致孕期和婴儿早期的新治疗策略，最终可能有助于减轻儿童肥胖的流行。