The Impact of Maternal Health and Diet on Development of Fetal Metabolic Systems

描述（由申请人提供）：在过去的20年里，儿童中可预防的代谢性疾病的发病率显著增加。目前，几乎没有信息来确定潜在的原因，或者治疗或饮食干预是否可以成功地预防或减少肥胖妊娠儿童的代谢健康风险。这些研究将使用非人类灵长类动物（NHP）模型来研究母体代谢健康和饮食不良对发育中的胎儿代谢系统发育的影响，以及其产后生长发育和对饮食引起的肥胖和糖尿病的易感性。在这些研究中，将长期维持高脂肪和高热量（HFD）饮食来培育NHPs。NHP是一个关键模型，因为它具有与人类胎儿相似的发育特征，包括胎盘功能、大脑和胰腺发育。该提案将重点关注胎盘、胰腺、肝脏和肌肉，因为这些构成了对体重和葡萄糖稳态的正常调节至关重要的核心代谢系统。该假说认为，从胎盘功能障碍开始的异常（即血液流动、细胞因子产生和营养物质输送）直接影响后代所有代谢系统的发育，从而导致代谢疾病的终生风险。此外，据推测，补充减少氧化应激和炎症的药物将防止或减轻妊娠期间在HFD中观察到的结构、代谢和分子紊乱，并将防止灵长类后代代谢系统的异常发育。这些研究将确定在怀孕前从高脂肪饮食完全转变为低脂肪饮食是否可以减少或预防胎儿发育并发症。研究还将确定，用于预防炎症和氧化应激的鱼油或白藜芦醇膳食补充剂是否也能提供类似的保护。这些研究将确定与母体代谢健康和饮食不良相关的胎儿发育风险和并发症。此外，这些研究将测试膳食补充剂/干预措施，这些补充剂/干预措施可以迅速转化为可能有助于预防或减少儿童代谢疾病的临床应用。

DESCRIPTION (provided by applicant): 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. Furthermore, 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 of the similarities in development, as well as structure and function of metabolic systems