Role of liver and visceral fat in glucose and lipid metabolism during pregnancy

描述(由申请人提供)：肥胖和胰岛素抵抗是不良母婴妊娠结局的重要风险因素。肝脏和内脏脂肪储备相互之间呈正相关，并与全身肥胖呈正相关。此外，两者都与非怀孕成年人的胰岛素敏感性指标呈负相关。虽然有限的现有证据表明怀孕有助于中枢和内脏脂肪含量的变化，但尚未发表的研究评估内脏和肝脏脂肪含量的变化，或者肝脏和内脏脂肪含量是否与随着怀孕提前而出现的全身、肝脏和骨骼肌胰岛素敏感性的降低有关。鉴于过量的腹部和肝脏脂肪(非酒精性脂肪性肝病)是进展为严重肝病、2型糖尿病和冠状动脉疾病的重要危险因素，了解怀孕如何促进内脏和肝脏脂肪储存具有重要的公共卫生意义。此外，灵长类动物的研究已经将饮食脂肪增加与胎盘功能受损联系在一起。我们所缺乏的是研究人体、局部和异位脂肪增加以及伴随的胰岛素抵抗在人类胎盘功能或胎儿大小受损的表现中所起的作用的翻译研究。为了填补这些重要的知识空白，我们将研究妊娠早期到晚期内脏和肝脏脂肪的变化(通过磁共振成像和光谱分析)，测量全身和器官的胰岛素敏感性(通过胰岛素钳技术进行评估)，代谢组学来检测代谢的脂质和葡萄糖中间体的标志性变化，以及子宫胎盘灌注和胎儿人体测量学(通过孕34周的超声波评估)。为了评估改变模型，我们将对60名(20名瘦、20名超重和20名肥胖)正常糖耐量(NGT)孕妇进行前瞻性队列研究，在12-16周和32-36周进行评估。为了评估这些参数在妊娠晚期NGT和妊娠期糖尿病(GDM)之间的差异，我们将对怀孕32-36周的30名妇女(15名NGT，15名GDM)进行病例对照研究。这项研究在以下几个方面具有创新性：1)首次在胰岛素敏感性的同时前瞻性评估怀孕期间的内脏脂肪和肝脏脂肪，并评估内脏脂肪和肝脏脂肪的差异。 这些研究包括：1)在患有妊娠期糖尿病和不患有妊娠期糖尿病的妇女之间进行研究；2)结合先进的成像和钳位方法来了解特定器官在糖脂代谢方面的紊乱；3)这将是首次将这些成像和钳位测量与脂肪毒性和子宫胎盘功能的新的代谢迹象相结合，从而测试肥胖和胰岛素抵抗之间的重要联系与先前仅在动物模型中证实的胎儿编程之间的重要联系。

DESCRIPTION (provided by applicant): Obesity and insulin resistance are significant risks factors for adverse maternal and fetal pregnancy outcomes. Liver and visceral fat stores are positively correlated with each other and with whole body adiposity. Additionally, both are negatively correlated with measures of insulin sensitivity in nonpregnant adults. While limited available evidence suggests that pregnancy contributes to changes in central and visceral fat content, no published studies have evaluated change in visceral and liver fat content or whether liver and visceral fat content are associated with the decrease in whole body, hepatic, and skeletal muscle insulin sensitivity seen with advancing pregnancy. Given that excess abdominal and liver fat (nonalcoholic fatty liver disease) are significant risk factors for progression to severe liver disease, type 2 diabetes, and coronary artery disease, understanding how pregnancy contributes to visceral and liver fat stores is of substantial public health importance. Furthermore, primate studies have linked increased diet fat and impaired placental function. What we are lacking are translational studies that examine what roles increased body, regional, and ectopic fat, and accompanying insulin resistance plays in the manifestation of impaired placental function or fetal size in humans. To fill these important gaps in knowledge, we will examine changes in visceral and liver fat (assessed by magnetic resonance imaging and spectroscopy) from early to late pregnancy with measures of whole body and organ-specific insulin sensitivity (assessed by insulin clamp technique), metabolomics to detect signature alterations in lipid and glucose intermediates of metabolism, and uteroplacental perfusion and fetal anthropometrics (assessed by ultrasound at 34 weeks gestation). To evaluate change models, we will conduct a prospective cohort study of 60 (20 lean, 20 overweight, and 20 obese) normal glucose-tolerant (NGT) pregnant women assessed at 12-16 weeks gestation and again at 32-36 weeks gestation. To evaluate how these parameters differ between women with NGT and gestational diabetes (GDM) in the third trimester of pregnancy, we will perform a case-control study of 30 women (15 NGT, 15 GDM) at 32-36 weeks' gestation. This study is innovative in several ways: 1) it is the first to prospectively assess visceral and liver fat durin pregnancy concurrently with insulin sensitivity and to assess differences in visceral and liver fat stores between women with and without GDM; 2) it combines state of the art imaging and clamp methodology to understand organ-specific disturbances in glucose and lipid metabolism; and 3) it will be the first study to combine these imaging and clamp measures with measures of novel metabolic signatures of liptoxicity and uteroplacental function, thereby testing an important link between obesity and insulin resistance with programming of fetus previously only demonstrated in animal models.