Insulin Resistance and Glucose and Lipid Metabolism in Pregnancy

描述(由申请者提供)：该项目的长期目标是描述和了解怀孕前和怀孕早期母体代谢与肥胖妇女胎儿生长/肥胖增加有关的机制。肥胖正在成为一种流行病，不仅在世界发达国家，而且在发展中国家，不仅影响成年人和青少年，甚至可能影响新生儿。这项提议有三个具体目标。具体目的1是评价母体肥胖对胎盘生长和基因表达的影响。我们假设，由于胰岛素敏感性降低，肥胖女性的胰岛素反应增强，这可能通过调节脂肪因子和脂肪基因的表达而导致胎盘生长增加。具体目的2是评估瘦身妇女从孕前到妊娠早期母体白色脂肪组织(WAT)脂代谢的纵向变化。我们假设，在妊娠早期，脂肪分解减少，胰岛素对脂肪分解的抑制增加，导致母体脂肪量增加。因此，Wat的增加导致脂肪因子的调节增加，从而降低了胰岛素敏感性。具体目标3是评估肥胖妇女从孕前到怀孕早期母体WAT脂代谢的纵向变化。我们假设，由于肥胖女性相对于瘦弱女性胰岛素敏感性降低，她们增加了基础脂肪分解，减少了孕前和怀孕期间对脂肪分解的抑制，从而增加了转移到胎儿的脂肪可获得性。因为没有增加或减少母亲的WAT，所以脂肪因子的表达没有改变或减少，导致胰岛素敏感性与妊娠前相比没有变化或增加。通过在体内进行详细的生理学研究，结合体外实验，采用前瞻性的纵向研究设计，我们将能够以确定的方式检验我们的假设。我们将根据我们的人口标准数据，确定观察到的胎儿肥胖的生理变化和新生儿结局的机制，肥胖定义为脂肪组织的增加。如果我们的假设是正确的，那么这些研究将为可能预防胎儿肥胖的干预性研究提供合理的基础，我们认为肥胖是一个重要的风险因素，即代谢综合征在人群中的患病率增加。

DESCRIPTION (provided by applicant): The long term objectives of this project are to characterize and understand the mechanisms by which pregravid and early pregnancy maternal metabolism relate to increased fetal growth/adiposity among obese women. Obesity is becoming an epidemic not only in the developed nations of the world but also in developing countries, affecting not only adults and adolescents but possibly even newborns. This proposal has 3 specific aims. Specific aim 1 is to evaluate the affect of maternal obesity on placental growth and gene expression in vivo and in vitro. We hypothesize that obese women because of decreased insulin sensitivity have an increased insulin response which results in increased placental growth possibly through modulation of adipokine and lipid gene expression. Specific aim 2 is to evaluate the longitudinal changes in maternal white adipose tissue (WAT) lipid metabolism from pregravid to early pregnancy in lean women. We hypothesize that in early pregnancy there is decreased lipolysis, increased insulin suppression of lipolysis of WAT resulting in increased accretion of maternal fat mass. Consequently, the increase in WAT results in increased modulation of adipokines resulting in decreased insulin sensitivity. Specific aim 3 is to evaluate the longitudinal changes in maternal WAT lipid metabolism from pregravid to early pregnancy in obese women. We hypothesize that because obese women have decreased insulin sensitivity relative to lean women, they have increased basal lipolysis, decreased suppression of lipolysis both pregravid and in pregnancy resulting in increased lipid availability for transfer to the fetus. Because there is no accretion or loss of maternal WAT, there is no change or decrease in expression of adipokines resulting in either no change or increase in insulin sensitivity relative to pregravid measures. By performing the detailed physiologic studies in vivo combined with the in vitro experiments in a prospective longitudinal study design, we will be able to test our hypotheses in a definitive manner. We will identify mechanisms for the observed physiologic changes and neonatal outcome of fetal obesity, defined as an increase in adipose tissue based on our population normative data. If our hypotheses are correct, these studies will then provide us with a rational basis for interventional studies to possibly prevent fetal obesity which we believe is a significant risk factor the increased prevalence of the metabolic syndrome in the population.