Legacy of excess: consequences of maternal obesity for the adult offspring
Legacy of excess: consequences of maternal obesity for the adult offspring
复制标题
DOI：
10.1113/jp276762
复制
发表时间：
2018-08
期刊：
影响因子：
--
通讯作者：
A. Forhead
中科院分区：
文献类型：
--
作者：
A. Forhead
发育规划是指出生前和新生儿早期的环境影响发育中的生理系统的结构和功能，并对成年后的健康产生长期影响的过程。当发育规划的概念和“健康和疾病的发育起源”首次提出时，该假设侧重于低营养环境对后代生理的影响（Barker, 2004）。流行病学数据显示，与出生时体重正常的婴儿相比，出生时体重偏小的足月婴儿成年后更容易患代谢和心血管疾病，包括II型糖尿病、非酒精性脂肪性肝病（NAFLD）和冠心病。营养不良的胎儿似乎形成了一种“节俭表型”，这在短期内有利于生存，但却使后代在以后的生活中容易出现代谢和心血管功能障碍。最近，注意力已转向产妇营养过剩的后果，这已成为发达世界日益关注的问题。在英国，大约50%的育龄妇女超重或肥胖，五分之一的妇女在怀孕期间肥胖。在广泛的流行病学、临床和实验动物研究中，研究了怀孕期间营养过剩的影响（Glastras et al. 2018）。研究表明，母亲肥胖会影响胎盘、早期胚胎和胎儿的发育，并对后代产生短期和长期的影响。在肥胖母亲所生的婴儿中，生长受限和巨大儿的发生率更高，这些婴儿在出生体重谱的两端，在以后的生活中有更大的代谢和心血管功能障碍的风险。有趣的是，在人类和动物的后代中，在出生前暴露于母亲营养不足或营养过剩的环境中，都有类似的长期结果，这两种环境都不是正常生长发育的最佳环境。多种相互作用机制可能涉及母体肥胖的发育规划，包括暴露于母体代谢物和具有表观遗传和其他影响的脂肪源性细胞因子。孕妇肥胖与全身和组织炎症因子水平升高、胎盘炎症、氧化应激和内皮功能障碍标志物升高有关。在这一期中，Lomas-Soria及其同事研究了可能导致母亲肥胖大鼠模型后代肝功能障碍和NAFLD的机制（Lomas-Soria et al. 2018）。大鼠从断奶、怀孕和哺乳期开始喂食高脂肪、致肥性饮食。年轻的成年后代是高胰岛素血症和高甘油三酯血症，并显示出更高的体脂肪和肝脏甘油三酯含量比喂养对照组的后代。与雌性后代相比，雄性后代在肝脏增大、组织学和脂肪含量方面发生了更显著的变化。该研究还提供了关于潜在分子变化的重要信息，以补充在怀孕期间喂食高脂肪饮食的非人灵长类动物胎儿中的发现（McCurdy et al. 2009）。在胎儿肝脏中，NAFLD的早期症状表现为甘油三酯含量增加、氧化应激和糖异生途径的激活。这些变化与胎儿循环中炎症细胞因子的高浓度有关。综上所述，这些研究表明，母亲的高脂肪饮食会影响胎儿的肝脏发育，这种影响会持续到成年，从而增加NAFLD的风险。在对后代肝脏转录组进行生物信息学分析后，Lomas-Soria等人（2018）报告了一些与母亲肥胖有关的差异表达基因。在雄性后代中，1317个基因被下调，而雌性后代中只有24个基因被下调，两性中有40-50个基因被上调。许多受影响的基因与胰岛素信号和肝脏中的糖脂代谢有关。这些发现突出了未来研究的一系列新目标。还需要进一步的研究来确定这些分子变化是否与肝功能障碍的发育程序有关，还是次要的。值得注意的是，在雄性和雌性后代中，只有一个共同基因对母亲肥胖表现出一致的反应。因此，在妊娠合并母体肥胖的情况下，可能存在雄性和雌性后代对宫内环境的敏感性差异和/或在随后的肝功能障碍编程中存在不同的分子通路。两性之间观察到的应答基因的不同特征和肝脏表型的差异也加强了分别考虑男性和女性数据的重要性。两性二态性是发育编程的一个公认特征（Dearden et al. 2018）。性别依赖结果的机制尚不清楚，但在实验动物研究中已经报道了胎盘、下丘脑和脂肪组织内表观遗传过程的差异。Lomas-Soria等人（2018）的研究有助于我们理解母体肥胖对肝功能的发育规划，并提出了一些重要问题：保护雌性后代免受母体肥胖对肝脏结构和功能的不利影响的机制是什么？在男性后代中观察到的分子变化在多大程度上导致了包括NAFLD在内的发病率和寿命方面的“男性劣势”？NAFLD和II型糖尿病的发病率，特别是在儿童和青少年中，与全球肥胖的流行程度相当，这一关系可能起源于生命早期。进一步的研究对于绘制宫内环境对个体生命过程中代谢功能和分子机制的影响以及评估其影响至关重要
Developmental programming is the process whereby the environment before birth and in early neonatal life influences the structure and function of developing physiological systems with long lasting consequences for health in adult life. When the concept of developmental programming and the ‘Developmental Origins of Health and Disease’ was first proposed, the hypothesis focused on the effects of a low nutrient environment on offspring physiology (Barker, 2004). Epidemiological data showed that term infants born small were more likely to suffer from metabolic and cardiovascular disease in adult life, including type II diabetes, non-alcoholic fatty liver disease (NAFLD) and coronary heart disease, compared to those born of average weight. The fetus exposed to undernutrition appears to develop a ‘thrifty phenotype’ which is beneficial for survival in the short term, but which predisposes the offspring to metabolic and cardiovascular dysfunction in later life. More recently, attention has turned to the consequences of maternal overnutrition, which has become an increasing concern in the developed world. In the UK, approximately 50% of women of reproductive age are overweight or obese, and 1 in 5 women are obese during pregnancy. The effects of overnutrition during pregnancy have been examined in a wide range of epidemiological, clinical and experimental animal studies (Glastras et al. 2018). Maternal obesity has been shown to impact the development of the placenta, early embryo and fetus with consequences for the offspring in the short and longer term. Higher incidences of both growth restriction and macrosomia are observed in babies born to obese mothers, and these infants at opposite ends of the birth weight spectrum are at greater risk of metabolic and cardiovascular dysfunction in later life. Interestingly, there are similar long term outcomes in human and animal offspring that were exposed to either maternal underor overnutrition before birth, both suboptimal environments for normal growth and development. A variety of interacting mechanisms may be involved in developmental programming by maternal obesity, including exposure to maternal metabolites and adipose-derived cytokines with epigenetic and other effects. Maternal obesity is associated with elevated systemic and tissue levels of inflammatory factors, and markers of inflammation, oxidative stress and endothelial dysfunction in the placenta. In this issue, Lomas-Soria and colleagues have examined the mechanisms that may be responsible for hepatic dysfunction and NAFLD in the offspring of a rat model of maternal obesity (Lomas-Soria et al. 2018). Rats were fed a high fat, obesogenic diet from weaning and during pregnancy and lactation. The young adult offspring were hyperinsulinaemic and hypertriglyceridaemic, and showed greater body adiposity and hepatic triglyceride content than the offspring of dams fed the control diet. More marked changes in liver enlargement, histology and fat content were observed in the male compared to female offspring. The study also provides important information on underlying molecular changes to complement the findings in the fetuses of non-human primates fed a high fat diet during pregnancy (McCurdy et al. 2009). In the fetal liver, early signs of NAFLD were characterised by increased triglyceride content, oxidative stress and activation of gluconeogenic pathways. These changes were associated with high concentrations of inflammatory cytokines in the fetal circulation. Taken together, these studies demonstrate that a maternal high fat diet influences hepatic development in the fetus with effects that persist into adulthood to increase the risk of NAFLD. Following bioinformatic analysis of the offspring liver transcriptome, Lomas-Soria et al. (2018) report a number of differentially expressed genes in response to maternal obesity. In male offspring, 1317 genes were down-regulated compared to only 24 genes in the female offspring, and 40–50 genes were up-regulated in both sexes. Many of the genes affected were related to insulin signalling, and glucose and lipid metabolism in the liver. These findings highlight a range of new targets for future investigation. Further studies are also required to determine whether these molecular changes are responsible for, or are secondary to, the developmental programming of hepatic dysfunction. Remarkably, only one common gene showed a consistent response to maternal obesity in both male and female offspring. Therefore, in pregnancies complicated by maternal obesity, there may be differences in the sensitivity of male and female offspring to the intrauterine environment and/or separate molecular pathways in the subsequent programming of hepatic dysfunction. The distinct profiles of responsive genes and differences in hepatic phenotype observed between the sexes also reinforce the importance of considering data from males and females separately. Sexual dimorphism is a well-recognised feature of developmental programming (Dearden et al. 2018). The mechanisms responsible for sex-dependent outcomes are unclear, but differences in epigenetic processes within the placenta, hypothalamus and adipose tissue have been reported in experimental animal studies. The study by Lomas-Soria et al. (2018) contributes to our understanding of developmental programming of hepatic function by maternal obesity and raises a number of important questions: What are the mechanisms that protect the female offspring from the adverse effects of maternal obesity on hepatic structure and function? To what extent do the molecular changes observed in male offspring contribute to the ‘male disadvantage’ in morbidity, including NAFLD, and longevity? The alarming rates of NAFLD and type II diabetes, especially in children and adolescents, parallel the global epidemic in obesity, and this relationship may originate in early life. Further research is vital to map the effects of the intrauterine environment on metabolic function and the molecular mechanisms responsible over the life course of an individual and to assess the