Maternal obesity and cardiometabolic health in the offspring

母亲肥胖与后代心脏代谢健康

• 批准号: 9925261
• 负责人: Abhinav Diwan
• 金额: $ 60.86万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925261
• 关键词: 1 year old; Adult; Architecture; Autophagocytosis; Biological Assay; Caliber; Cardiac; Cardiac Myocytes; Cardiac health; Cardiovascular Diseases; Cardiovascular system; Cell Nucleus; Cells; Child; Complications of Diabetes Mellitus; Cytoplasm; DNA; Data; Development; Diet; Eating; Echocardiography; Embryo Transfer; Emission-Computed Tomography; Epigenetic Process; Event; Experimental Models; Fatty acid glycerol esters; Female; Fertilization in Vitro; Generations; Goals; Health; Heart; Heart Abnormalities; Heart failure; Heritability; Human; Hypertension; Impairment; In Vitro; Inherited; Knowledge; Lead; Left; Left Ventricular Dysfunction; Left Ventricular Function; Levocarnitine; Lipids; Liver diseases; Measures; Metabolic; Metabolic syndrome; Metabolism; Mitochondria; Mitochondrial DNA; Molecular; Morphology; Mus; Myocardial dysfunction; Myocardium; Nature; Non obese; Nuclear; Obese Mice; Obesity; Oocytes; Outcome; Overweight; Oxygen Consumption; Pharmacology; Phenotype; Positron-Emission Tomography; Preventive measure; Reactive Oxygen Species; Resolution; Risk; Rodent; Skeletal Muscle; Somatic Cell; Stress; Sucrose; Testing; Therapeutic; Thinness; Tissues; Transmission Electron Microscopy; Ventricular; Weaning; Weight; Woman; Work; X-Ray Computed Tomography; adverse outcome; cardiometabolism; cardiovascular disorder risk; design; global health; glucose uptake; heart function; improved; male; maternal obesity; methylome; mitochondrial dysfunction; mouse model; new therapeutic target; next generation; nonhuman primate; novel; obese mothers; offspring; prevent; sex; transcriptome; transcriptome sequencing; transmission process; zygote

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.

肥胖是一个全球性的健康问题，导致心血管疾病、糖尿病和相关疾病的风险增加。 并发症此外，肥胖和超重妇女的后代比那些出生时 正常体重的女性在一岁时肥胖;患有代谢综合征，高血压和肝脏 幼儿期患有心血管疾病;成人期患有心血管疾病。母性的机制 后代心脏损害的程序尚不清楚，阻碍了制定策略， 防止他们。我们建立了一种小鼠模型，其中母体高脂肪/高糖（HF/HS）饮食诱导的肥胖 会导致后代心脏畸形具体来说，尽管断奶后吃标准饮食， 喂食HF/HS饮食的雌性小鼠（F0）的雌性F1后代出现显著的左心室功能受损 功能定义为缩短分数降低和左心室内径增加。 我们的目标是确定它们在多大程度上是跨代遗传的， 这些影响发生的机制。我们的理由是，如果我们能确定负责的机制， 这种母体心脏损害的程序，我们也许能够制定治疗措施，以防止 这种使人衰弱的线粒体功能障碍。我们假设，这种线粒体表型导致心脏功能的扰动是跨代的，因为它是由卵母细胞传递。我们预计，这种现象是由于 核或线粒体DNA（mtDNA）的表观遗传变化。我们还假设卵母细胞内 活性氧积累和/或脂质积累是表观遗传传递的原因，并且是直接的遗传传递。 母亲HF/HS饮食的结果。这三个目标旨在检验这些假设。的结果予以 研究将提供一个明确的机制来解释传播，这将导致新的治疗目标。 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 来改善下一代的健康。