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

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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.