Department of Pediatrics, Perinatal Research Center
University of Colorado Denver
metabolism, molecular endocrinology, and developmental origins
Grants: 1) CNRU/NORC Pilot Award: Mechanisms for fetal hepatic programming during intrauterine growth restriction
Description of Research
1. Effect of IUGR on fetal glucose metabolism. We are investigating the mechanisms responsible for increased glucose production in the IUGR fetus using our sheep model of IUGR. Molecular studies at the tissue level are being performed to understand the effect of IUGR at the mRNA, protein, and chromatin level and we are using studies in freshly isolated hepatocytes to test mechanisms and evaluate the persistence of the IUGR phenotype in culture. These studies will provide novel information regarding the effect of IUGR on the regulation of fetal glucose metabolism and fetal programming of diabetes.
2. Role of fetal hypoglycemia in regulation of hepatic glucose production. We will evaluate the effect of fetal hypoglycemia on regulating glucose production in the liver by comparing our IUGR fetal sheep model and our chronic fetal hypoglycemic model induced my maternal insulin infusion. We plan to identify changes at the molecular level (RNA, protein, chromatin) and also perform studies in primary fetal hepatocytes.
3. Effect of IUGR on nutrient sensing in fetal tissues. We are investigating the effect of IUGR on nutrient sensing pathways in fetal liver and skeletal muscle. This will include detailed molecular analyses at the RNA and protein level combined with in utero studies in our fetal sheep models.
4. Effect of maternal high fat diet on hepatic metabolism in offspring. This is a collaborative project with Jed Friedman and the National Primate Research Center. We are evaluating the effect of a maternal high fat diet on the offspring during fetal and postnatal life. Specifically, we are looking at the molecular and epigenetic mechanisms underlying impaired hepatic glucose and lipid metabolism.
1-2 Most Significant Publications
1. SR Thorn, Regnault TR, Brown LD, Rozance PJ, Keng J, Roper M, Wilkening RH, Hay WW, and Friedman JE. 2009. Intrauterine growth restriction increases fetal hepatic gluconeogenic capacity and reduces messenger ribonucleic acid translation initiation and nutrient sensing in fetal liver and skeletal muscle. Endocrinology 150:3021-30.
Primary Focus Area (if part of the obesity initiative)
· Maternal/Developmental Origins of Obesity
Secondary Focus Areas (if part of the obesity initiative)
· Metabolic Dysregulation and Comorbidities associated with obesity
· Obesity cell biology
Benefit of CNRU
The CNRU provides an opportunity for enhanced interaction and collaboration with other CNRU investigators and pilot awards for new investigators, like me, to develop research programs.
CNRU Cores Used
CNRU CollaborationsHay, Friedman, McCurdy, Brown, Rozance.