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

改善肥胖妊娠期间母亲代谢状况并预防后代心脏代谢和行为缺陷的干预措施

• 批准号: MR/N029259/1
• 负责人: Paul Taylor
• 金额: $ 50.27万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN029259%2F1
• 关键词: Interventions; improve; maternal; metabolic; profile

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.

墨西哥是世界上肥胖率最高的国家之一，儿童肥胖率也是最高的。母亲肥胖现在是唯一最大的产科风险因素，人们现在普遍认识到，母亲肥胖不仅是妊娠结局(如先兆子痫、妊娠期糖尿病和巨大儿)的风险因素，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。最近的一篇里程碑式的论文报告称，孕期母亲肥胖与成年后代全因死亡率的增加有关，特别是心血管事件死亡率的增加(Reynolds等人，2013年)。因此，现在比以往任何时候都更加重要的是，我们了解肥胖流行病对孕妇的后果，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后代代谢健康的可改变的风险因素，并为干预提供了机会，以遏制日益增长的儿童肥胖潮，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”强调了早期生活中的大量环境暴露，这些环境暴露可能会改变一个人一生的健康状况。人类人口研究表明，母亲怀孕和出生后早期的饮食和荷尔蒙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，动物研究为发育规划现象及其在后代长期健康和疾病中的作用提供了宝贵的机制洞察和原则性证明。墨西哥的赞布拉诺博士和伦敦国王学院的泰勒博士的团队多年来一直在发育规划领域工作，并对饮食和生活方式干预措施感兴趣，以改善肥胖怀孕的母亲新陈代谢状况，防止后代出现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，白藜芦醇和多聚葡萄糖，他们打算在妊娠期肥胖的大鼠模型上测试安全性和有效性(治疗潜力)。白藜芦醇是一种多酚类化合物，是一类具有多种生物活性和抗氧化性的天然植物化合物。另一方面，聚葡萄糖是一种具有低血糖指数和益生菌特性的可溶性纤维。在初步研究中，研究小组已经在怀孕期间肥胖的动物模型中显示了这两种化合物对不良代谢和荷尔蒙状况的有利影响。合作将利用互补的啮齿动物模型来促进对这些化合物在改善肥胖妊娠母亲代谢状况方面的有效性和安全性的理解，以及它们对后代心血管(高血压)代谢(肥胖和糖尿病)和行为缺陷(认知功能和ADHD)的疾病预防潜力。对这两种有希望的化合物进行干预，可以想象到通过不同的途径发挥作用，也将提供对怀孕期间肥胖如何导致儿童及以后的肥胖和相关疾病的洞察和机械理解。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，而国王大学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，这项令人兴奋的牛顿基金提案寻求开发共同的研究兴趣，以加强我们两个团队之间的合作。它将为我们的研究工作带来附加值，提供技术和知识转让，同时在五年内为我们的墨西哥合作伙伴提供重要的能力建设和临床翻译。

项目成果

Maternal Resveratrol Treatment Protects Against Leptin-Resistance In Male Offspring of Obese Rat Dams But Impairs Leptin Sensitivity In Offspring Of Control Dams

母体白藜芦醇治疗可防止肥胖大鼠雄性后代的瘦素抵抗，但会损害对照大鼠后代的瘦素敏感性

• 发表时间: 2019
• 作者: Itani N

Resveratrol intervention in obese pregnant rats improves maternal and offspring metabolism

白藜芦醇干预肥胖妊娠大鼠可改善母体和子代代谢

• 发表时间: 2019
• 作者: Hernandez A

Effect of maternal resveratrol administration on offspring sugar preference and glucose tolerance in a rat model of obese pregnancy

母体白藜芦醇给药对肥胖妊娠大鼠模型后代糖偏好和糖耐量的影响

• 发表时间: 2019
• 作者: Itani N

Role of amygdala kisspeptin in pubertal timing in female rats.

杏仁核亲吻肽在雌性大鼠青春期时机中的作用。

• DOI: 10.1371/journal.pone.0183596
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Adekunbi DA;Li XF;Li S;Adegoke OA;Iranloye BO;Morakinyo AO;Lightman SL;Taylor PD;Poston L;O'Byrne KT
• 通讯作者: O'Byrne KT

Effect of Maternal Resveratrol Administration on Offspring Sugar Preference in a Rat Model of Obese Pregnancy

母体白藜芦醇给药对肥胖妊娠大鼠模型后代糖偏好的影响

• 发表时间: 2019
• 作者: Itani N