Interventions to improve maternal metabolic profile in obese pregnancy and prevent cardio-metabolic and behavioural deficits in future generations

墨西哥是世界上肥胖率最高的国家之一，也是儿童肥胖率最高的国家。产妇肥胖现在是单一的最大的产科风险因素，现在人们广泛认识到，产妇肥胖不仅是妊娠结局的风险因素（例如先兆子痫，妊娠糖尿病和巨大胎儿），而且也是儿童长期健康的风险因素，肥胖和相关合并症的风险增加。最近一篇具有里程碑意义的论文报道了妊娠期母体肥胖与成年后代全因死亡率的增加相关，特别是心血管事件死亡率的增加（Reynolds et al.，2013年）的报告。因此，现在比以往任何时候都更重要的是，我们了解肥胖流行病对孕妇的后果，不仅是怀孕结果，而且是对下一代心血管健康的潜在影响。怀孕期间的饮食和营养是影响后代代谢健康的可改变的风险因素，并提供了干预机会，以遏制儿童肥胖的增长趋势，并影响下一代的心血管和心理健康。“健康和疾病的发育规划假说”强调了生命早期的许多环境暴露，这些暴露可以改变一个人一生的健康状况。人群研究表明，母亲的饮食和激素环境在怀孕和出生后早期的影响，在成年期的疾病风险，并广泛支持动物研究，这是非常宝贵的机制洞察力和原则证明的现象，发育编程及其作用的后代长期，Zambrano博士在墨西哥的研究小组和Taylor博士在伦敦国王学院的研究小组已经在发育规划领域工作了多年，并且在饮食和生活方式干预以改善产妇代谢状况方面有着共同的兴趣在肥胖的怀孕和预防心脏代谢和行为缺陷的后代。研究小组已经确定了两种候选化合物，白藜芦醇和聚葡萄糖，他们打算在妊娠肥胖大鼠模型中测试其安全性和有效性（治疗潜力）。白藜芦醇是一种多酚类化合物，是天然存在的植物化合物中的一种，具有多种生物活性和抗氧化特性。另一方面，聚葡萄糖是一种可溶性纤维，具有低血液指数和益生菌特性。在初步研究中，研究小组已经在妊娠期肥胖的动物模型中显示了这两种化合物对不良代谢和激素谱的有益作用。该合作将采用互补的啮齿动物模型，以进一步了解这些化合物在改善妊娠期肥胖的母体代谢谱方面的有效性和安全性，以及它们在预防心血管疾病方面的潜力。（高血压）代谢（肥胖和糖尿病）和行为缺陷（认知功能和多动症）在未来几代人。这两种有前途的化合物的干预，可以想象通过不同的途径发挥作用，也将提供洞察力和机制的理解，如何在怀孕期间肥胖可以引起肥胖和相关疾病的儿童及以后。这项建议将很容易转化为对肥胖孕妇的临床研究，特别是在墨西哥，国王大学的妇女健康学术中心在对孕妇进行大规模临床试验方面拥有丰富的经验。因此，这个令人兴奋的牛顿基金提案旨在利用共同的研究兴趣，加强我们团队之间的合作。它将为我们的研究工作带来附加值，提供技术和知识转让，同时在五年的时间内为我们的墨西哥合作伙伴和临床翻译提供重要的能力建设。

The prevalence of obesity in Mexico is one of the highest in the world, and the highest for childhood obesity. Maternal obesity is now the single biggest obstetric risk factor, and it is now widely recognised that maternal obesity is not only a risk factor for pregnancy outcomes (e.g. pre-eclampsia, gestational diabetes and fetal macrosomia) but also for the long term health of the child, with increased risk of obesity and related comorbidities. A recent landmark paper reported maternal obesity in pregnancy was associated with an increase in all-cause mortality in adult offspring and specifically increased mortality from cardiovascular events (Reynolds et al., 2013). It is therefore, now more important than ever before that we understand the consequences of the obesity epidemic for pregnant women, not just in terms of pregnancy outcome, but also in terms of the potential impact on the cardiovascular health of the next generation. Diet and nutrition in pregnancy are modifiable risk factors for offspring metabolic health and offer the opportunity for intervention to stem the growing tide of childhood obesity and impact on the cardiovascular and mental health of the next generation. The 'developmental programming of health and disease hypothesis' has highlighted numerous environmental exposures in early life that can modify an individuals health over a lifetime. Human population studies demonstrate influences of maternal diet and hormonal environment in pregnancy and early post-natal life on disease risk in adulthood and are extensively supported by animal studies which have been invaluable in providing mechanistic insight and proof of principle into the phenomenon of developmental programming and its role in offspring long-term health and disease.Dr Zambrano's team in Mexico and Dr Taylor's group at King's College London have worked in the field of developmental programming for many years and have a shared interest in diet and lifestyle interventions to improve maternal metabolic profile in obese pregnancy and prevent cardio-metabolic and behavioural deficits in the offspring. The teams have identified two candidate compounds, resveratrol and polydextrose which they intend to test for safety and efficacy (therapeutic potential) in a rat model of obesity in pregnancy. Resveratrol is a polyphenolic compound and one of a diverse group of naturally occurring plant compounds with numerous biological activities and anti-oxidant properties. Polydextrose on the other hand, is a soluble fibre with low glycaemic index and pro-biotic properties. In preliminary studies the teams have shown beneficial effects of both these compounds on adverse metabolic and hormonal profiles in an animal model of obesity in pregnancy.The collaboration will employ complementary rodent models to advance understanding of the efficacy and safety of these compounds in improving maternal metabolic profiles in obese pregnancy and their disease-preventive potential for cardiovascular (high blood pressure) metabolic (obesity and diabetes) and behavioural deficits (cognitive function and ADHD) in future generations. Interventions with these two promising compounds, conceivably acting through divergent pathways, will also provide insight and mechanistic understanding of how obesity in pregnancy can beget obesity and related disorders in childhood and beyond. This proposal will readily translate to clinical studies in obese pregnant women particularly in Mexico and the Women's Health Academic Centre at King's has extensive experience of conducting large scale clinical trials in pregnant women. This exciting Newton fund proposal therefore seeks to exploit common research interests, to forge stronger collaboration between our groups. It will bring added value to our research efforts, provide technology and knowledge transfer, whilst providing vital capacity building for our Mexican partners and clinical translation within a five year time-frame.