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: 8449685
• 负责人: LINDA Anne BARBOUR
• 金额: $ 48.47万
• 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/8449685
• 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.

描述（由申请人提供）：令人信服的动物和人类流行病学证据支持，母亲肥胖和糖尿病在宫内创造了一个促进胎儿过度生长的环境，从而改变了出生时的身体成分，并可能增加儿童肥胖的风险。虽然妊娠期糖尿病（GDM）引起的高血糖被认为是影响胎儿脂肪增加的主要燃料来源，但孕龄大（LGA）婴儿数量的惊人增长主要是由不符合妊娠期糖尿病诊断标准的肥胖妇女所生。作为我们的R56试点资助的结果，我们证明了从妊娠早期到妊娠晚期母体空腹甘油三酯（TG）的变化与婴儿DXA测量的新生儿肥胖之间存在显著的强相关性（r=0.91; p=0.001），独立于母体BMI。这种相关性甚至比我们在控制饮食的情况下通过72小时连续血糖监测（CGMS）检测隐匿性高血糖的最可靠的血糖指数更强；(r = 0.79; p = 0.01)。此外，我们观察到，尽管有强大的胰岛素反应和抑制游离脂肪酸（FFA），但液体餐后TG漂移完全钝化，表明TG清除迅速。我们的R56试点研究结果强调，有必要进一步研究FFA的可用性，作为了解妊娠早期和晚期伴有和不伴有GDM的瘦弱和肥胖孕妇的新生儿肥胖的关键胎儿燃料。我们还将跟踪婴儿，以评估肥胖表型在一岁时的持久性。根据我们的初步数据，我们假设新生儿肥胖的预测是：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活性增加，白色脂肪组织（WAT） LPL活性降低，从而增加胎儿FFA可用性；3)隐性高血糖与GDM状态无关。此外，我们假设我们可以通过胎儿超声3D体积参数在妊娠28周预测新生儿肥胖，并且肥胖表型将持续到一岁，由婴儿饮食脂肪摄入促进。在Aim 1中，我们将研究空腹和餐后状态下TG颗粒的来源。在Aim 2中，我们将测定母体WAT和胎盘中的LPL活性，以评估这些组织的溶脂活性。在Aim 3中，我们将继续研究符合GDM标准的肥胖女性与不符合GDM标准的肥胖女性在控制饮食期间的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，作为一项探索性目的，我们对婴儿进行了为期一年的随访，并使用DXA和PEAPOD确定肥胖表型是否持续存在，还是受到婴儿饮食脂肪摄入量的影响。我们相信我们的R01再提交的发现可能会挑战目前关于胎儿脂肪增加的燃料背后的想法，并最终导致在子宫内和婴儿早期安全有效的干预，这可能有助于降低儿童肥胖的风险。