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根本原因，或者治疗或饮食干预是否可能成功地预防或减少肥胖怀孕儿童的代谢健康风险。这些研究将使用非人灵长类动物(NHP)模型来调查不良的母体代谢健康和饮食对发育中的胎儿代谢系统发育的影响，以及产后生长发育和饮食引起的肥胖和糖尿病的易感性。在这些研究中，繁殖的NHP将长期维持在高脂肪和高卡路里(HFD)的饮食中。NHP是一个关键的模型，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。这项建议将重点放在胎盘、胰腺、肝脏和肌肉上，因为这些构成了对正常调节体重和血糖动态平衡至关重要的核心代谢系统。假说是，以胎盘功能障碍(即血流、细胞因子产生和营养输送)开始的异常直接影响后代所有代谢系统的发展，从而导致终生代谢性疾病的风险。此外，假设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期间观察到的结构、代谢和分子障碍，并将防止灵长类后代代谢系统的异常发展。这些研究将确定怀孕前从高脂饮食到低脂饮食的完全转变是否可以减少或预防胎儿发育中的并发症。还将确定添加鱼油或白藜芦醇的膳食补充剂是否会提供类似的保护作用，以防止炎症和氧化应激。这些研究将确定与母亲代谢健康和饮食不良相关的发育中胎儿的风险和并发症。此外，这些研究将测试可以快速转化到临床的膳食补充剂/干预措施，即MAV有助于预防或减少儿童代谢性疾病。 公共卫生相关性：产妇健康和营养不良与儿童患代谢性疾病的风险增加有关。然而，导致儿童肥胖和糖尿病增加的潜在并发症和机制尚不清楚。由于代谢系统在发育、结构和功能上的相似性，NHP是识别这些机制的关键模型

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