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，儿童肥胖率最高。产妇肥胖现在是最大的单一产科风险因素，现在人们普遍认识到，产妇肥胖不仅是妊娠结局（如先兆子痫、妊娠糖尿病和胎儿巨大儿）的一个风险因素，而且也是儿童长期健康的一个风险因素，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，怀孕期间的母亲肥胖与成年后代全因死亡率的增加有关，特别是心血管事件导致的死亡率增加（Reynolds等，2013）。因此，现在比以往任何时候都更重要的是，我们要了解肥胖流行病对孕妇的影响，不仅是在怀孕结果方面，而且在对下一代心血管健康的潜在影响方面。怀孕期间的饮食和营养是影响后代代谢健康的可改变的危险因素，并提供了干预的机会，以阻止日益增长的儿童肥胖趋势，并对下一代的心血管和心理健康产生影响。“健康和疾病的发展规划假说”强调了生命早期的许多环境暴露，这些环境暴露可以改变个人一生的健康状况。人口研究表明，孕期和产后早期产妇饮食和激素环境对成年后疾病风险的影响，并得到了动物研究的广泛支持，这些研究在提供机制见解和原理证明方面非常宝贵，有助于了解发育规划现象及其在后代长期健康和疾病中的作用。桑布拉诺博士在墨西哥的研究小组和泰勒博士在伦敦国王学院的研究小组在发育规划领域工作了多年，并对饮食和生活方式干预有共同的兴趣，这些干预可以改善肥胖怀孕期间母亲的代谢状况，防止后代的心脏代谢和行为缺陷。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，他们打算在妊娠期肥胖大鼠模型中测试它们的安全性和有效性（治疗潜力）。白藜芦醇是一种多酚类化合物，是多种天然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，聚葡萄糖是一种具有低血糖指数和益生特性的可溶性纤维。在初步研究中，研究小组在妊娠期肥胖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影响。此次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肥胖妊娠期母体代谢谱方面的有效性和安全性，以及它们在后代中预防心血管（高血压）代谢（肥胖和糖尿病）和行为缺陷（认知功能和多动症）的潜力。使用这两种有前景的化合物进行干预，可以想象，它们通过不同的途径起作用，也将为妊娠期肥胖如何导致儿童期及以后的肥胖和相关疾病提供见解和机制理解。这一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，国王学院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寻求利用共同的研究兴趣，在我们的小组之间建立更强有力的合作。它将为我们的研究工作带来附加值，提供技术和知识转移，同时为我们的墨西哥合作伙伴提供重要的能力建设，并在五年的时间框架内进行临床转化。

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.