The past several decades have revealed a devasting trend- the dramatic increase in preventable diseases in children, including obesity, diabetes, cardiovascular disease and nonalcoholic fatty liver disease (NAFLD). The general hypothesis of this proposal is that diet and metabolic health (such as obesity and diabetes) during pregnancy and the early neonatal period significantly contribute to the development of metabolic diseases in children, predisposing them to widespread health risks throughout life. We have developed a nonhuman primate (NHP) model of high fat/calorie diet-induced maternal obesity/diabetes in which to determine the immediate and long-term effects on body weight homeostasis in offspring. The specific focus of this proposal is the melanocortin neurons in the hypothalamus, which are critical for the homoeostatic feedback control of food intake and energy balance in response to peripheral adiposity signals. We predict that consumption of a high fat/calorie diet during pregnancy, resulting in maternal hyperlipidemia and insulin resistance, will cause an abnormal development of these neurons during in the fetal period, leading to a long-term reprogramming. We also predict that this phenotype will be exacerbated by exposure to the same diet during the postnatal period. With these developmental abnormalities, we expect the offspring to be predisposed to early onset obesity and ultimately diabetes These studies will use a variety of in vivo and in vitro physiolgical assays, combined with anatomical and biochemical assays to determine the effects of maternal high fat diet induced obesity/diabetes on the development of hypothalamic melanocortin system in the offspring during the late fetal and juvenile stages. Finally, we will investigate if feeding a healthy diet to obese/diabetic NHPs specifically during pregnancy can protect against the development of metabolic abnormalties in the offspring. With these studes, we hope to demonstrate that simply being overweight and eating a high fat diet causes metabolic disease in babies;a maternal phenotype that matches the majority of pregnancies in the United States. Furthermore, that eating a healthy diet specifically during pregnancy, even in obese/diabetic animals, can protect against the development of these diseases. This information will be critical for designing a viable prevention and has enormous public health implications

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK079194-04
Application #
7858016
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Silva, Corinne M
Project Start
2007-07-15
Project End
2011-09-29
Budget Start
2010-06-01
Budget End
2011-09-29
Support Year
4
Fiscal Year
2010
Total Cost
$762,585
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
True, Cadence; Arik, Anam; Lindsley, Sarah et al. (2018) Early High-Fat Diet Exposure Causes Dysregulation of the Orexin and Dopamine Neuronal Populations in Nonhuman Primates. Front Endocrinol (Lausanne) 9:508
True, Cadence; Dean, Tyler; Takahashi, Diana et al. (2018) Maternal High-Fat Diet Effects on Adaptations to Metabolic Challenges in Male and Female Juvenile Nonhuman Primates. Obesity (Silver Spring) 26:1430-1438
True, C; Takahashi, D; Kirigiti, M et al. (2017) Arcuate nucleus neuropeptide coexpression and connections to gonadotrophin-releasing hormone neurones in the female rhesus macaque. J Neuroendocrinol 29:
Kjaergaard, M; Nilsson, C; Secher, A et al. (2017) Differential hypothalamic leptin sensitivity in obese rat offspring exposed to maternal and postnatal intake of chocolate and soft drink. Nutr Diabetes 7:e242
Chadderdon, S M; Belcik, J T; Bader, L et al. (2016) Vasoconstrictor eicosanoids and impaired microvascular function in inactive and insulin-resistant primates. Int J Obes (Lond) 40:1600-1603
Chadderdon, Scott M; Belcik, J Todd; Bader, Lindsay et al. (2016) Temporal Changes in Skeletal Muscle Capillary Responses and Endothelial-Derived Vasodilators in Obesity-Related Insulin Resistance. Diabetes 65:2249-57
Juan De Solis, Alain; Baquero, Arian F; Bennett, Camdin M et al. (2016) Postnatal undernutrition delays a key step in the maturation of hypothalamic feeding circuits. Mol Metab 5:198-209
Sullivan, Elinor L; Riper, Kellie M; Lockard, Rachel et al. (2015) Maternal high-fat diet programming of the neuroendocrine system and behavior. Horm Behav 76:153-61
Rivera, Heidi M; Kievit, Paul; Kirigiti, Melissa A et al. (2015) Maternal high-fat diet and obesity impact palatable food intake and dopamine signaling in nonhuman primate offspring. Obesity (Silver Spring) 23:2157-64
Baquero, Arian F; Kirigiti, Melissa A; Baquero, Karalee C et al. (2015) Developmental changes in synaptic distribution in arcuate nucleus neurons. J Neurosci 35:8558-69

Showing the most recent 10 out of 42 publications