Mechanisms by which Obesity in Pregnancy Leads to Obesity in Offspring

妊娠期肥胖导致后代肥胖的机制

基本信息

批准号：
8432856
负责人：
Rebecca A Simmons
金额：
$ 31.72万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8432856
关键词：
Address Adipocytes Affect Age Animals Antioxidants Birth Cell Lineage Chromatin DNA Methylation Data Desire for food Development Diabetes Mellitus Diet Elderly Embryo Energy Metabolism Environment Epigenetic Process Event Exhibits Fatty Acids Fatty acid glycerol esters Female Fetus Fostering Gene Expression Genes Genome Growth and Development function Health Human Incidence Inflammation Insulin Resistance Lead Life Link Measures Mediating Mesenchymal Stem Cells Messenger RNA Metabolic Microarray Analysis Modification Mothers Neonatal Newborn Infant Obesity Oxidative Stress Placenta Plasma Play Polyunsaturated Fatty Acids Predisposition Pregnancy Pregnant Women Process Rattus Risk Rodent Role Saturated Fatty Acids Staging Testing Time Tissues United States Up-Regulation Woman adipocyte differentiation blastocyst chromatin remodeling embryo/fetus feeding fetal high risk histone modification lipid biosynthesis offspring postnatal preimplantation prenatal exposure prevent programs public health relevance pup

项目摘要

DESCRIPTION (provided by applicant): An increasing number of studies in humans and rodents demonstrate that the abnormal intrauterine metabolic milieu associated with obesity in pregnancy can have long-lasting effects on the development of obesity and diabetes in offspring. Both human and animal studies show that maternal obesity significantly increases fetal and neonatal adiposity and that offspring of obese mothers have a very high risk of developing obesity in later life. We have found that offspring of female rats fed a cafeteria diet either prior to pregnancy, or prior to and during pregnancy have increased fat mass and insulin resistance at 2 weeks of age compared to offspring of dams fed ordinary rat chow (preliminary data). Fat mass is also increased in pups of rat chow fed dams that are cross-fostered to an obese dam. However, the increase in fat mass of cross-fostered pups is not as great as in pups that were exposed to maternal obesity during pregnancy, suggesting that prenatal exposures may be more important than postnatal exposure in programming obesity in the offspring. The mechanisms linking maternal obesity to the later development of obesity in the offspring are unknown. Maternal obesity results in increased plasma levels of saturated fatty acids and decreased levels of long-chain polyunsaturated fatty acids (PUFAs). This abnormal fatty acid profile causes oxidative stress and inflammation. Therefore, these findings and our previous studies lead us to hypothesize that in maternal obesity, oxidative stress induces epigenetic modifications of key adipogenic genes in the embryo thereby potentiating the adipocyte differentiation program by enhancing lineage commitment as well as terminal differentiation in the offspring. We will test these hypotheses by the following specific aims: Specific Aim 1: Determine whether the pre-implantation stage of development represents the critical window of susceptibility to the effects of maternal obesity. Specific Aim 2: Demonstrate that maternal obesity potentiates adipogenesis in the offspring. Specific Aim 3: Determine the mechanisms by which epigenetic modifications increase expression of adipogenic genes. Specific Aim 4: Demonstrate that oxidative stress causes obesity in the offspring of the obese dam.

描述（由申请人提供）：越来越多的人类和啮齿动物研究表明，与妊娠期肥胖相关的异常宫内代谢环境可能对后代肥胖和糖尿病的发展产生长期影响。人类和动物研究表明，母亲肥胖会显着增加胎儿和新生儿的肥胖率，并且肥胖母亲的后代在以后的生活中患肥胖症的风险非常高。我们发现，与喂养普通大鼠食物的母鼠后代相比，在怀孕前或怀孕前和怀孕期间喂养食堂饮食的雌性大鼠后代在两周龄时脂肪量和胰岛素抵抗有所增加（初步数据）。与肥胖母鼠交叉饲养的老鼠饲料喂养的母鼠的幼崽的脂肪量也会增加。然而，交叉寄养的幼崽脂肪量的增加不如怀孕期间暴露于母体肥胖的幼崽那么大，这表明产前暴露可能比产后暴露对后代肥胖的影响更重要。将母亲肥胖与后代肥胖相关联的机制尚不清楚。母亲肥胖会导致血浆饱和脂肪酸水平升高和长链多不饱和脂肪酸（PUFA）水平降低。这种异常的脂肪酸谱会导致氧化应激和炎症。因此，这些发现和我们之前的研究使我们假设，在母亲肥胖中，氧化应激诱导胚胎中关键脂肪形成基因的表观遗传修饰，从而通过增强后代的谱系定型和终末分化来增强脂肪细胞分化程序。我们将通过以下具体目标来检验这些假设：具体目标 1：确定胚胎着床前发育阶段是否代表了对孕产妇肥胖影响易感性的关键窗口期。具体目标 2：证明母亲肥胖会增强后代的脂肪生成。具体目标 3：确定表观遗传修饰增加脂肪形成基因表达的机制。具体目标 4：证明氧化应激会导致肥胖母鼠的后代肥胖。