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

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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.