Regulation of Maternal Fuel Supply and Neonatal Adiposity

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，母亲肥胖和糖尿病创造了促进胎儿过度生长的宫内环境，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。尽管妊娠期糖尿病(GDM)引起的高血糖被认为是影响胎儿脂肪堆积的主要燃料来源，但巨大胎龄(LGA)婴儿数量的惊人增长主要是由不符合GDM诊断标准的肥胖妇女出生的。由于我们的R56试点资助，我们证明了母亲从妊娠早期到晚期的空腹甘油三酯(TG)变化与婴儿DXA测量的新生儿肥胖症之间存在显著的相关性(r=0.91p=0.001)，与母亲的体重指数无关。这种相关性甚至比我们在受控饮食期间72小时连续血糖监测(CGMS)用于检测隐性高血糖的最稳健的血糖指数更强；(r=0.79；p=0.01)。此外，我们观察到，尽管有强劲的胰岛素反应和游离脂肪酸(FFA)的抑制，但在流质餐后，餐后TG漂移完全钝化，这表明TG清除迅速。我们的R56试验结果强调了进一步研究FFA作为关键的胎儿燃料的必要性，以了解患有和不患有妊娠期糖尿病的瘦型和肥胖型孕妇的新生儿肥胖症，包括妊娠早期和晚期。我们还将跟踪观察婴儿，以评估出生一年后肥胖表型的持久性。根据我们的初步数据，我们假设新生儿肥胖是由以下因素预测的：1)由于极低密度脂蛋白-甘油三酯可获得性增加和母亲膳食脂肪摄入量增加，妊娠期间空腹甘油三酯增加，2)胎盘LPL活性增加和白色脂肪组织(WAT)LPL活性降低，从而增加胎儿FFA的可获得性，以及3)与GDM状态无关的隐性高血糖。此外，我们假设我们可以通过胎儿超声三维体积参数预测妊娠28周的新生儿肥胖，肥胖表型将持续到一岁，婴儿饮食脂肪摄入量促进了肥胖的发生。在目标1中，我们将调查空腹和餐后状态下甘油三酯颗粒的来源。在目标2中，我们将测定孕妇WAT和胎盘中LPL的活性，以评估这些组织的脂解活性。在目标3中，我们将继续调查符合GDM标准的肥胖女性和不符合GDM标准的肥胖女性在控制饮食期间GCMS血糖指数是否存在差异。在目标4中，我们将把最重要的母体变量纳入多元回归模型，以预测新生儿肥胖。最后，作为一个探索性目标，我们对婴儿进行了一年的跟踪调查，并使用DXA和Peapod来确定肥胖表型是否持续存在，或者是受到婴儿膳食脂肪摄入量的影响。我们相信，R01重新提交的结果可能会挑战导致胎儿脂肪堆积的燃料背后的当前想法，并最终导致安全有效的宫内和早期婴儿干预，这可能有助于降低儿童肥胖的风险。 公共卫生相关性：近些年来，出生时胎龄较大且有患儿童肥胖症风险的婴儿数量急剧上升。因此，了解宫内环境如何将过多的血脂和葡萄糖输送到肥胖孕妇的胎儿是很重要的，这些孕妇可能不符合目前的妊娠期糖尿病标准。从这些研究中获得的怀孕期间和生命第一年期间的代谢和饮食信息可能会导致新的治疗策略，无论是在怀孕期间还是在婴儿早期，最终可能有助于缓解儿童肥胖症的流行。

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.