Maternal obesity and cardiometabolic health in the offspring

母亲肥胖与后代心脏代谢健康

基本信息

批准号：
9762209
负责人：
Abhinav Diwan
金额：
$ 60.82万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/9762209
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

项目摘要

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，肥胖和超重女性的后代比肥胖和超重女性所生的后代更有可能体重正常的女性一岁时就会肥胖；患有代谢综合征、高血压和肝病年幼时患病；成年后患有心血管疾病。母体的机制后代心脏损伤的编程尚不清楚，阻碍了策略的制定阻止他们。我们开发了一种小鼠模型，其中母亲高脂肪/高蔗糖（HF/HS）饮食诱导的肥胖导致后代心脏异常。具体来说，尽管断奶后饮食标准，但成人喂养 HF/HS 饮食的雌性小鼠 (F0) 的雌性 F1 后代左心室明显受损功能由缩短分数减少和左心室内径增加定义。我们的目标是确定它们跨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能够确定负责的机制这种母亲对心脏损害的编程，我们也许能够制定治疗措施来预防这种使人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跨代的，因为它是由卵母细胞传播的。我们预计这种现象是由于核 DNA 或线粒体 DNA (mtDNA) 的表观遗传变化。我们还假设卵母细胞内 ROS 积累和/或脂质积累负责表观遗传传递，并且是直接的母亲 HF/HS 饮食的结果。这三个目标旨在检验这些假设。这些结果研究将提供一个明确的机制来解释这种传播，这将带来新的治疗靶点。我们的目标是这项工作将产生新的预防措施和潜在的药理产品以改善下一代的健康。