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
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