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

• 批准号: 7782226
• 负责人: Rebecca A Simmons
• 金额: $ 39.92万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/7782226
• 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

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. PUBLIC HEALTH RELEVANCE: Maternal obesity significantly increases fetal and neonatal adiposity and offspring of obese mothers have a very high risk of developing obesity in later life. This application will address the mechanisms underlying this phenomenon and determine if a diet enriched with antioxidants will prevent the development of obesity in the offspring. Since the incidence of obesity is rapidly increasing in the United States, these studies will have great impact on health.

描述(申请人提供)：越来越多的对人类和啮齿动物的研究表明，与怀孕期间肥胖相关的异常宫内代谢环境可以对后代肥胖和糖尿病的发展产生长期影响。人类和动物研究都表明，母亲肥胖会显著增加胎儿和新生儿的肥胖，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，无论是在怀孕前，还是在怀孕前和怀孕期间，雌性大鼠的后代与喂食普通大鼠食物的雌性大鼠的后代相比，在2周大时脂肪质量和胰岛素抵抗都有所增加(初步数据)。喂食母鼠的幼鼠的脂肪质量也会增加，这些母鼠被交叉饲养到肥胖的母狗身上。然而，交叉养育的幼崽脂肪质量的增加没有怀孕期间暴露于母体肥胖的幼崽那么大，这表明在后代编程肥胖方面，产前暴露可能比出生后暴露更重要。母体肥胖症与子代肥胖症后期发展之间的联系机制尚不清楚。母亲肥胖导致血浆饱和脂肪酸水平升高和长链多不饱和脂肪酸(PUFAs)水平下降。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引导我们假设，在母体肥胖中，氧化应激诱导胚胎中关键的成脂基因的表观遗传修饰，从而通过增强后代的谱系承诺和终末分化来增强脂肪细胞的分化计划。我们将通过以下具体目标来检验这些假说：具体目标1：确定植入前发育阶段是否代表对母体肥胖影响易感的关键窗口。具体目标2：证明母亲肥胖会促进后代的脂肪生成。具体目标3：确定表观遗传修饰增加成脂基因表达的机制。具体目标4：证明氧化应激导致肥胖母亲的后代肥胖。 公共卫生相关性：母亲肥胖会显著增加胎儿和新生儿的肥胖症，肥胖母亲的后代在以后的生活中患肥胖症的风险非常高。这项应用将解决这一现象的潜在机制，并确定富含抗氧化剂的饮食是否可以防止后代肥胖的发展。由于肥胖症在美国的发病率正在迅速增加，这些研究将对健康产生重大影响。