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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
3K01DK090199-03S1
Application #
8629874
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2010-09-30
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$862
Indirect Cost
$64
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Wesolowski, Stephanie R; Hay Jr, William W (2016) Role of placental insufficiency and intrauterine growth restriction on the activation of fetal hepatic glucose production. Mol Cell Endocrinol 435:61-8
Brown, Laura D; Wesolowski, Stephanie R; Kailey, Jenai et al. (2016) Chronic Hyperinsulinemia Increases Myoblast Proliferation in Fetal Sheep Skeletal Muscle. Endocrinology 157:2447-60
Brown, Laura D; Davis, Melissa; Wai, Sandra et al. (2016) Chronically Increased Amino Acids Improve Insulin Secretion, Pancreatic Vascularity, and Islet Size in Growth-Restricted Fetal Sheep. Endocrinology 157:3788-3799
Houin, Satya S; Rozance, Paul J; Brown, Laura D et al. (2015) Coordinated changes in hepatic amino acid metabolism and endocrine signals support hepatic glucose production during fetal hypoglycemia. Am J Physiol Endocrinol Metab 308:E306-14
Brown, Laura D; Rozance, Paul J; Bruce, Jennifer L et al. (2015) Limited capacity for glucose oxidation in fetal sheep with intrauterine growth restriction. Am J Physiol Regul Integr Comp Physiol 309:R920-8
Andrews, Sasha E; Brown, Laura D; Thorn, Stephanie R et al. (2015) Increased adrenergic signaling is responsible for decreased glucose-stimulated insulin secretion in the chronically hyperinsulinemic ovine fetus. Endocrinology 156:367-76
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
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

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