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

项目摘要/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，而且这一比例正在不断上升。儿童肥胖症的患病率在 令人震惊的比率，肥胖母亲所生的孩子患糖尿病、代谢疾病的风险更高 综合症和心血管疾病。来自各种物种的令人信服的证据表明，母体 肥胖对后代的新陈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子女心脏功能障碍的有限研究。心肌病 与线粒体疾病相关的疾病发生在20%-40%的儿童中，线粒体功能障碍更多 在肥胖儿童中普遍高于正常体重儿童。不幸的是，细胞和分子机制 人们对此仍然知之甚少。这项研究的长期目标是确定终生效应和机制 母体代谢环境异常与子代心脏代谢性疾病的关系 为通过母体运动预防儿童肥胖的治疗策略提供证据。我们有 最近在雌性小鼠中建立了孕前和妊娠期肥胖模型，在该模型中，雄性后代 患上葡萄糖耐受性和胰岛素抵抗的程度比雌性后代更大。解决性爱问题 作为生物学变量，雄性和雌性后代将被用来：1)在体内和体外评估 运动前后母亲肥胖对心脏收缩特性的影响；2)确定 肥胖母亲的心脏形态/结构改变和基因表达 没有运动；以及3)确定氧化应激和线粒体功能是潜在的 母体肥胖和运动对子代心脏代谢健康改变的机制。尽管 运动对心脏功能的长期有益影响在健康的正常体重中得到了很好的证明 据我们所知，我们的研究是第一次调查母体锻炼的作用 子代心脏功能及其强调性别差异的潜在机制 线粒体功能。这项拟议的研究结果将促进我们对母性 运动可以改变心脏结构、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。我们的建议很好 与美国国立卫生研究院减轻慢性病负担的使命相一致。

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.