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

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.

Maternal obesity and excessive gestational weight gain are the most common obstetric risk factors with direct implications for pregnancy outcome as well as the potential to heighten obesity and related disease risk in offspring. Maternal obesity in pregnancy is associated with an increase in all-cause mortality in adult offspring, specifically increasing mortality from cardiovascular events but also impacting quality of life through multiple comorbidities and mental health. Obesity prevalence in Mexico is one of the world's highest including childhood obesity with a 32% prevalence over 20 years of age. Effective public intervention and prevention health strategies are needed.
The academic beneficiaries of this proposal will be: the scientific community involved in research into the Developmental Origins of Health and Disease (DOHAD); Scientists and clinicians investigating the origins of obesity and related disorders; Scientists and clinicians investigating the origins of essential hypertension; Scientists and clinicians investigating the origins of cognitive development, ADHD and mental health; Scientists in academia and the pharmaceutical industry, and students with an interest in integrative physiology; Scientists and clinicians investigating the consequences of obesity in pregnant women, and the potential lifelong impact on the child;
The non-academic beneficiaries of this work include: Health professionals and policy makers responsible for the care of obese pregnant women and their children; the lay community, especially pregnant women and their children. Both partners Dr Paul Taylor (PT) and Dr Elena Zambrano (EZ) and also our project partner Professor Peter Nathanielsz (PN) are either members or Council members of the DOHAD society, and members of the advisory board of the journal of DOHAD, and have input into the organisation and content of international meeting and workshops often as keynote speakers, and have had input into policy making in this field.
Results will be communicated to the general scientific community through presentation at scientific meetings spanning the breadth of the disciplines involved to achieve a maximal target audience (e.g. DOHaD International Congress; Society for Gynecologic Investigation, Physiological Society, European Congress on Obesity, Society for Neuroscience Annual Meeting). Publication will be in the high impact peer reviewed journals with fast on-line access in which we are used to publishing (e.g. PLoS One, Cell Metabolism, Nature Medicine, PNAS). Tissues and data will be shared.
This proposal has potential for commercial application. The rat model of developmental programming by maternal obesity has already attracted interest from food commodity companies, including Tate and Lyle and Danone which have resulted in the award of two BBSRC Case Studentships. We have also had contract research projects with Nestle (Switzerland), testing novel dietary products in our rodent models of obese pregnancy. Should this project demonstrate that maternal consumption of either resveratrol or polydextrose during pregnancy and lactation has benefit in preventing obesity in the offspring, the model would be useful for testing supplements or enriched commercial foodstuffs.
In Mexico, Dr. Zambrano is invited frequently to radio shows (radio UNAM in the program health voice) to make people aware showing her principal findings. In addition our group participates in national meetings as an example The Annual National Institutes of Health Meeting, Annual Meeting of the Mexican Society of Endocrinology and Nutrition and Latinoamerican meetings as the Latinoamerican Reproductive Society Meeting and the Developmental Origins of Health and Disease Iberoamerican Congress. Dr. Zambrano has twice won the Nestle Prize in Mexico for the best paper on nutrition. She has also won the prize from the major food retailer Bimbo for all Latin America.