Sex differences in cardiometabolic health of offspring born from obese mothers with and without exercise

项目概要/摘要 肥胖是一种全球流行病;近60%的育龄妇女被认为超重或肥胖， 美国，而且这个比例还在不断上升。儿童肥胖症的患病率正在增加， 肥胖母亲所生的孩子患糖尿病、代谢性糖尿病和糖尿病的风险更高， 综合征和心血管疾病。来自不同物种的有力证据表明， 肥胖对后代的代谢健康产生负面影响，并影响各种系统;然而， 一项调查肥胖母亲所生后代心脏功能障碍的有限研究。心肌病 与线粒体疾病相关的发生在20-40%的儿童中，线粒体功能障碍更多 肥胖儿童的患病率高于正常体重儿童。不幸的是，细胞和分子机制 仍然知之甚少。这项研究的长期目标是确定终身影响和机制 潜在的异常母体代谢环境对后代心脏代谢疾病的影响 为通过母亲运动预防儿童肥胖的治疗策略提供依据。我们有 最近在雌性小鼠中建立了妊娠前和妊娠期肥胖模型，其中雄性后代 发展葡萄糖耐受不良和胰岛素抵抗的程度大于雌性后代。为了解决性问题 作为生物学变量，雄性和雌性后代将用于：1）体内和体外评价 心脏的收缩特性对母亲肥胖的反应，有和没有运动; 2）确定 肥胖母亲所生心脏的形态/结构改变和基因表达 没有运动;和3）确定氧化应激和线粒体功能作为基础 母体肥胖和运动对后代心脏代谢健康改变的机制。虽然 运动对心脏功能的长期有益作用在健康正常体重的人中得到了充分的证明 据我们所知，我们的研究是第一个调查产妇运动作用的研究。 对子代心功能的影响及其机制的研究 线粒体功能这项研究的结果将促进我们对孕产妇如何 运动改变心脏结构、线粒体功能和整体心脏功能;因此， 为预防与儿童肥胖相关的心脏病提供了一种新的干预措施。我们的提议很好 与NIH的使命一致，以减少慢性疾病的负担。

Project Summary/Abstract Obesity is a global epidemic; nearly 60% of women of reproductive age are considered overweight or obese in the U.S., and this percentage is continuously rising. The prevalence of childhood obesity is increasing at alarming rates, and children born from obese mothers have higher risks of developing diabetes, metabolic syndrome, and cardiovascular diseases. Compelling evidence from various species indicates that maternal obesity negatively influences the metabolic health of offspring and impacts various systems; however, there is a limited study investigating cardiac dysfunction of offspring born from obese mothers. Cardiomyopathy associated with mitochondrial disease occurs in 20-40% of children, and mitochondrial dysfunction is more prevalent in obese children than normal weight children. Unfortunately, the cellular and molecular mechanisms remain poorly understood. The long-term goal of this study is to determine the lifelong effects and mechanisms of an underlying abnormal maternal metabolic environment on cardiometabolic diseases in offspring and provide evidence for therapeutic strategy for preventing childhood obesity through maternal exercise. We have recently established pre-pregnancy and gestational obesity model in female mice in which the male offspring developed glucose intolerance and insulin resistance to a greater extent than female offspring. To address sex as a biological variable, both male and female offspring will be used to: 1) evaluate in vivo and in vitro contractile properties of the heart in response to maternal obesity with and without exercise; 2) determine morphological/structural alterations and gene expression of the heart born from obese mothers with and without exercise; and 3) determine oxidative stress and the mitochondrial function as the underlying mechanisms of maternal obesity and exercise on altered cardiometabolic health of offspring. Although the long-term beneficial effect of exercise on cardiac function is well documented in healthy normal weight population, to the best of our knowledge, our study is the first study to investigate the role of maternal exercise on cardiac function of offspring and the underlying mechanisms emphasizing on sex differences on mitochondrial function. The results of this proposed study will advance our knowledge of how maternal exercise modifies the cardiac structure, mitochondrial function, and overall heart function; and thus, could provide a new intervention for preventing heart disease associated with childhood obesity. Our proposal is well aligned with NIH’s mission to reduce the burden of chronic diseases.