My long-term goal is to understand how altered nutrient supply programs fetal metabolism and how these changes may persist after birth and increase susceptibility to adult metabolic disease. Decreased or increased nutrient supply during critical periods in fetal life can have a major impact on the development and function of tissues and organs which may have a permanent effect on nutrient sensing and increase susceptibility to metabolic disease in adult life. Our recent data demonstrate that glucose production and gluconeogenic gene expression, which are normally absent during fetal life, are strikingly up-regulated in the late gestation IUGR fetal sheep. Our data also indicate that insulin fails to suppress glucose production in the IUGR fetus, yet robustly increases whole body rates of glucose utilization and oxidation, suggesting that the IUGR fetus develops liver-specific insulin resistance but increased peripheral insulin action. This career development award will use integrative approaches in fetal physiology and metabolism combined with novel metabolomic, molecular, and epigenetic techniques to test the hypothesis that the IUGR fetus develops tissue specific adaptations in insulin sensitivity and metabolism necessary for survival at the expense of somatic growth. Specifically, I will acquire surgical skills for fetal hepatic and hindlimb catheter preparations and develop new tracer methodologies for measurement of glucose and lactate metabolism in the whole fetus and across specific tissues including the liver and hindlimb, representing skeletal muscle as its metabolically active component. I will develop NMR metabolomics techniques to measure tissue metabolites, including intermediates, cofactors, and substrates for glycolysis, gluconeogenesis, and the TCA cycle. At the molecular level, I will gain expertise in assays of nuclear function, gene regulation, and epigenetics to determine mechanisms for differential insulin sensitivity in liver and skeletal muscle. The core laboratories, faculty mentoring, and training plan outlined in this proposal will allow me to develop advanced training in the execution of these methods that are essential steps in the evolution of my career path aimed at understanding the mechanisms for fetal metabolic programming at the level of the whole animal, organ/tissue, and molecular level. These studies will provide novel information regarding glucose and lactate metabolism and insulin action in the IUGR fetus and the coordination of metabolism between the fetal liver and skeletal muscle. These studies will also generate important concepts about the early development of signaling proteins and pathways linking IUGR to increased glucose production and insulin resistance in the liver and mechanisms that promote glucose uptake and utilization in skeletal muscle.
These studies are essential in understanding the effects of IUGR on fetal metabolism and fundamental to developing novel tissue-specific strategies aimed at reversing and preventing the development of adverse metabolic adaptations before they contribute to later life metabolic diseases in adults who were IUGR.
|Roberts, Victoria H J; Pound, Lynley D; Thorn, Stephanie R et al. (2014) Beneficial and cautionary outcomes of resveratrol supplementation in pregnant nonhuman primates. FASEB J 28:2466-77|
|Brown, Laura D; Thorn, Stephanie R; Cheung, Alex et al. (2014) Changes in fetal mannose and other carbohydrates induced by a maternal insulin infusion in pregnant sheep. J Anim Sci Biotechnol 5:28|
|Brown, Laura D; Thorn, Stephanie R; O'Meara, Meghan C et al. (2014) A physiological increase in insulin suppresses muscle-specific ubiquitin ligase gene activation in fetal sheep with sustained hypoglycemia. Physiol Rep 2:|
|Thorn, Stephanie R; Baquero, Karalee C; Newsom, Sean A et al. (2014) Early life exposure to maternal insulin resistance has persistent effects on hepatic NAFLD in juvenile nonhuman primates. Diabetes 63:2702-13|
|Gadhia, Monika M; Maliszewski, Anne M; O'Meara, Meghan C et al. (2013) Increased amino acid supply potentiates glucose-stimulated insulin secretion but does not increase *-cell mass in fetal sheep. Am J Physiol Endocrinol Metab 304:E352-62|
|Thorn, Stephanie R; Brown, Laura D; Rozance, Paul J et al. (2013) Increased hepatic glucose production in fetal sheep with intrauterine growth restriction is not suppressed by insulin. Diabetes 62:65-73|
|Lavezzi, Jinny R; Thorn, Stephanie R; O'Meara, Meghan C et al. (2013) Increased fetal insulin concentrations for one week fail to improve insulin secretion or *-cell mass in fetal sheep with chronically reduced glucose supply. Am J Physiol Regul Integr Comp Physiol 304:R50-8|
|Maliszewski, Anne M; Gadhia, Monika M; O'Meara, Meghan C et al. (2012) Prolonged infusion of amino acids increases leucine oxidation in fetal sheep. Am J Physiol Endocrinol Metab 302:E1483-92|
|Thorn, Stephanie R; Rozance, Paul J; Brown, Laura D et al. (2011) The intrauterine growth restriction phenotype: fetal adaptations and potential implications for later life insulin resistance and diabetes. Semin Reprod Med 29:225-36|