Mechanisms by which Obesity in Pregnancy Leads to Obesity in Offspring

描述（由申请人提供）：越来越多的人类和啮齿动物研究表明，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很高。我们发现，与喂食普通大鼠食物的母鼠的后代相比，在怀孕前或怀孕前和怀孕期间喂食自助餐饮食的雌鼠的后代在2周龄时脂肪量和胰岛素抵抗增加（初步数据）。在与肥胖母鼠交叉饲养的大鼠饲料喂养母鼠的幼崽中，脂肪量也增加。然而，增加的脂肪量的交叉寄养的幼崽是不一样大的幼崽在怀孕期间暴露于母体肥胖，这表明，产前暴露可能比出生后暴露在编程肥胖的后代。母亲肥胖与后代肥胖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（PUFA）水平降低。这种不正常的脂肪酸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，在母体肥胖中，氧化应激诱导胚胎中关键成脂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计划。我们将通过以下具体目标来检验这些假设：具体目标1：确定胚胎植入前发育阶段是否代表对母体肥胖影响的敏感性的关键窗口。具体目标2：证明母体肥胖可增强后代的脂肪形成。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鼠后代肥胖。 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，肥胖母亲的后代在以后的生活中患肥胖症的风险很高。这项申请将解决这一现象的机制，并确定富含抗氧化剂的饮食是否会防止后代肥胖的发展。由于肥胖的发病率在美国迅速增加，这些研究将对健康产生很大影响。

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.