Maternal obesity and cardiometabolic health in the offspring

肥胖是一个全球性的健康问题，会增加患心血管疾病、糖尿病及相关疾病的风险 并发症。此外，肥胖和超重女性的后代比那些出生时更有可能 体重正常的女性在一岁时肥胖；患有代谢综合征、高血压和肝脏 儿童时期罹患心血管疾病；成年后患心血管疾病。母体致病机制 子代心脏损伤的编程尚不清楚，阻止了制定策略 阻止他们。我们建立了一种母体高脂肪/高蔗糖(HF/HS)饮食诱导肥胖的小鼠模型 会导致后代心脏异常。具体地说，尽管在断奶后吃标准饮食，但成年 喂食HF/HS饲料的雌性小鼠(F0)的雌性F1后代出现明显的左心室损害 功能定义为短轴缩短率减少和左心室内径增加。 我们在这里的目标是确定它们在多大程度上是跨代遗传的，以及 这些效应发生的机制。我们的理论基础是，如果我们能够确定负责 这种母体编程的心脏损伤，我们或许能够制定治疗措施，以防止 这种衰弱的线粒体功能障碍。我们推测，这种导致心脏功能紊乱的线粒体表型是跨代的，因为它是通过卵母细胞传递的。我们预计这一现象是由于 核或线粒体DNA(MtDNA)的表观遗传学变化。我们还假设卵母细胞内 ROS的积累和/或脂质的积累是表观遗传传递的罪魁祸首，是 母亲HF/HS饮食的结果。这三个目标旨在检验这些假设。这些研究的结果 研究将提供一个明确的机制来解释这种传播，这将导致新的治疗靶点。 我们的目标是这项工作将导致新的预防措施和潜在的药理产品 提高下一代的健康水平。

Obesity is a global health problem, leading to increased risk for cardiovascular disease, diabetes, and related complications. Additionally, the offspring of obese and overweight women are more likely than those born to normal-weight women to be obese at one year of age; to have metabolic syndrome, hypertension, and liver disease as young children; and to have cardiovascular disease as adults. The mechanisms of maternal programming of cardiac impairment in the offspring are unclear, preventing development of strategies to prevent them. We have developed a mouse model in which maternal high fat/high sucrose (HF/HS) diet-induced obesity leads to cardiac abnormalities in the offspring. Specifically, despite eating a standard diet after weaning, adult female F1 offspring of female mice (F0) fed a HF/HS diet developed significantly impaired left ventricular function as defined by decreased fractional shortening and increased left ventricular inner diameter. Our objectives here are to determine the extent to which they are inherited transgenerationally and the mechanism by which these effects occur. Our rationale is if we can determine the mechanism responsible for this maternal programming of cardiac impairment, we may be able to develop therapeutic measures to prevent this debilitating mitochondrial dysfunction. We hypothesize that this mitochondrial phenotype leading to the perturbation of cardiac function is transgenerational since it is transmitted by the oocyte. We anticipate that this phenomenon is due to epigenetic changes to either the nuclear or mitochondrial DNA (mtDNA). We also hypothesize that intra-oocyte ROS accumulation and/or lipid accumulation are responsible for the epigenetic transmission and are the direct result of maternal HF/HS diet. The three aims are designed to test these hypotheses. The results of these studies will provide a clear mechanism to explain the transmission, which will lead to new therapeutic targets. It is our goal that this work will result in novel preventative measures and potentially pharmacological products to improve the health of the next generation.