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.

肥胖是一个全球健康问题，导致心血管疾病，糖尿病及相关的风险增加 并发症。此外，肥胖和超重女性的后代比出生的后代更有可能 正常体重妇女在一岁时肥胖；患有代谢综合征，高血压和肝脏 小孩的疾病；并患有心血管疾病作为成年人。母亲的机制 后代中心脏障碍的编程尚不清楚，从而阻止了制定策略 防止他们。我们已经开发了一种小鼠模型，其中孕妇高脂肪/高蔗糖（HF/HS）饮食诱导的肥胖症 导致后代心脏异常。特别是，尽管断奶后吃了标准饮食，但成人 雌性小鼠的雌性F1后代（F0）喂养HF/HS饮食的左心室显着受损 功能是由分数缩短减少和左心室内径增加而定义的。 我们在这里的目标是确定它们是跨世代遗传的程度以及 这些影响发生的机制。我们的理由是我们是否可以确定负责的机制 这种对心脏障碍的孕产妇编程，我们可能能够制定治疗措施以防止 这种衰弱的线粒体功能障碍。我们假设这种导致心脏功能扰动的线粒体表型是转世的，因为它是由卵母细胞传播的。我们预计这种现象是由于 对核或线粒体DNA（mtDNA）的表观遗传学变化。我们还假设拟人体内细胞 ROS的积累和/或脂质积累负责表观遗传传播，是直接的 母体HF/HS饮食的结果。这三个目标旨在检验这些假设。这些结果 研究将为解释传播提供明确的机制，这将导致新的治疗靶标。 我们的目标是这项工作将导致新颖的预防措施和潜在的药理学产品 改善下一代的健康。