The incidence of preventable metabolic diseases in children has increased markedly over the past 2 decades. Currently, there is little information to determine the underlying causes or whether therapeutic or dietary interventions might be successful at preventing or reducing metabolic health risks in children from obese pregnancy. These studies will use a nonhuman primate (NHP) model to investigate the impact of poor maternal metabolic health and diet on the development of metabolic systems in the developing fetus, as well as its postpartum growth, development, and susceptibility to diet induced obesity and diabetes. For these studies, breeding NHPs will be chronically maintained on a diet high in fats and calories (HFD). The NHP is a critical model as it shares developmental features similar to human fetuses, including placental function, brain, and pancreas development. This proposal will focus on the placenta, pancreas, liver and muscle as these form the core metabolic systems that are critical for normal regulation of body weight and glucose homeostasis. The hypothesis is that abnormalities beginning with placental dysfunction (i.e., blood flow, cytokine production and nutrient delivery) directly impact the development of all metabolic systems in the offspring that contribute to life-long risk for metabolic disease. Furthermore, it is hypothesized that supplementation with agents that reduce oxidative stress and inflammation will prevent or attenuate the structural, metabolic, and molecular disturbances observed during pregnancy while on a HFD, and will prevent the abnormal development of metabolic systems in primate offspring. These studies will determine if a complete dietary switch from the HFD to a low fat diet just prior to pregnancy can reduce or prevent complications in fetal development. It will also be determined if dietary supplements with either fish oil or resveratrol, to prevent inflammation, oxidative stress, will provide similar protection. These studies will identify the risks and complications in the developing fetus associated with poor maternal metabolic health and diet. Futhermore, these studies will test dietary supplements/interventions that can be quickly translated to the clinic that mav help prevent or reduce metabolic diseases in children.

Public Health Relevance

Poor maternal health and nutrition are associated with an increased risk of metabolic diseases in children. However, the underlying complications and mechanisms that lead to the increase in obesity and diabetes in children is poorly understood. The NHP is a critical model to identify these mechanisms because ofthe simlarities in development, as well as structure and function of metabolic systems

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Resource-Related Research Projects (R24)
Project #
5R24DK090964-03
Application #
8284456
Study Section
Special Emphasis Panel (ZDK1-GRB-R (O2))
Program Officer
Silva, Corinne M
Project Start
2010-09-25
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$1,595,849
Indirect Cost
$502,337
Name
Oregon Health and Science University
Department
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Soto, Susan M; Blake, Amy C; Wesolowski, Stephanie R et al. (2017) Myoblast replication is reduced in the IUGR fetus despite maintained proliferative capacity in vitro. J Endocrinol 232:475-491
Friedman, Jacob E (2017) The maternal microbiome: Cause or consequence of obesity risk in the next generation? Obesity (Silver Spring) 25:497-498
Wesolowski, Stephanie R; Kasmi, Karim C El; Jonscher, Karen R et al. (2017) Developmental origins of NAFLD: a womb with a clue. Nat Rev Gastroenterol Hepatol 14:81-96
Tolcher, Mary Catherine; Chu, Derrick M; Hollier, Lisa M et al. (2017) Impact of USPSTF recommendations for aspirin for prevention of recurrent preeclampsia. Am J Obstet Gynecol 217:365.e1-365.e8
Jonscher, Karen R; Stewart, Michael S; Alfonso-Garcia, Alba et al. (2017) Early PQQ supplementation has persistent long-term protective effects on developmental programming of hepatic lipotoxicity and inflammation in obese mice. FASEB J 31:1434-1448
Aamodt, Kristie I; Powers, Alvin C (2017) Signals in the pancreatic islet microenvironment influence ?-cell proliferation. Diabetes Obes Metab 19 Suppl 1:124-136
O'Neil, Derek S; Stewart, Christopher J; Chu, Derrick M et al. (2017) Conditional postnatal deletion of the neonatal murine hepatic circadian gene, Npas2, alters the gut microbiome following restricted feeding. Am J Obstet Gynecol 217:218.e1-218.e15
Nash, Michael J; Frank, Daniel N; Friedman, Jacob E (2017) Early Microbes Modify Immune System Development and Metabolic Homeostasis-The ""Restaurant"" Hypothesis Revisited. Front Endocrinol (Lausanne) 8:349
Kahr, Maike K; Suter, Melissa A; Ballas, Jerasimos et al. (2016) Geospatial analysis of food environment demonstrates associations with gestational diabetes. Am J Obstet Gynecol 214:110.e1-9
Roberts, Victoria H J; Lo, Jamie O; Salati, Jennifer A et al. (2016) Quantitative assessment of placental perfusion by contrast-enhanced ultrasound in macaques and human subjects. Am J Obstet Gynecol 214:369.e1-8

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