Maternal over-nutrition and offspring health: role of translational programming of insulin action

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The developmental origins of health and disease hypothesis links the intrauterine environment to long term health of offspring. There is evidence from human and animal studies that metabolic health of offspring is adversely affected by maternal obesity and diabetes during pregnancy. Using a mouse model of maternal diet-induced obesity we found that exposure to an obesogenic environment in utero led to the development of insulin resistance in young adult life. This was associated with altered expression of insulin signalling proteins in muscle, liver and adipose tissue. Notably, there was a marked decrease in IRS-1 protein in adipose tissue without any change in IRS-1 mRNA. Using primary cultured pre-adipocytes we showed that this reflects decreased synthesis of IRS-1 protein and that it is paralleled by an increased level of miRNA-126 that targets IRS-1 mRNA. We therefore hypothesise that maternal diet-induced obesity programmes adipose tissue insulin action in offspring through cell autonomous, post-transcriptional mechanisms that influence levels of IRS-1 and other proteins. The overall aim of this project is to elucidate the molecular mechanisms underlying this programming. We will take a global approach to identify miRNAs in adipose tissue that are programmed by maternal over-nutrition and identify targets of these miRNAs using a combination of bioinformatics, RNA-Seq and Ago2 immunoprecipitation. We will then define the role of selected miRNAs, including miR-126, in programming adipose tissue insulin sensitivity and function, by using miR mimics and antagonists. Finally, we will establish whether normalisation of maternal insulin in obese dams can prevent programming of adipocytes.
These studies will advance understanding of developmental programming arising from maternal over-nutrition and how such programming might be ameliorated. Most importantly, our experiments in animal models will inform debate on how to manage the corresponding human condition.

This proposal falls within the BBSRC strategic priority Ageing Research Lifelong Health and Wellbeing and specifically is within the scope of Fundamental research on the biology of ageing and its modulation by diet, physical activity and developmental factors. The proposal addresses two of the key issues identified and seeks to make an impact on both of these:
i) Diet, physical activity and health during ageing, and the need to understand the mechanisms by which diet and physical activity influence health across the lifecourse.
ii) Developmental factors and health during ageing, and the need to encourage research that investigates how early developmental factors may influence health during ageing, including the specific challenges to understand how nutritional exposures are recorded and transmitted through subsequent generations of cells and how this memory is translated into altered function in later life.
Academic impact
Developmental origins of health and disease is an expanding field in which UK research has so far been at the forefront. It cuts across many disciplines, most obviously physiology, nutrition and public health, with an urgent need for greater understanding at the biochemical level. The proposal therefore has potential to make a major academic impact by increasing knowledge of the molecular mechanisms linking maternal diet to metabolic phenotype of offspring. In addition to advancing knowledge, the research will involve development of new databases of miRNAs and their targets that will be broadly applicable in academia. On-going collaborations with other institutions in the UK and Europe will provide potential for extension of findings into other human cohort studies and animal models and in systems biology approaches. The research will provide cross-disciplinary training for the PDRAs, and opportunities for enhancing teaching and learning of undergraduate and postgraduate students through seminars and projects.
Economic and societal impacts
The research aims to define the network of miRNAs and their targets in adipose tissue that are programmed in offspring as a consequence of maternal obesity, predisposing to insulin resistance and metabolic disease in later life. These miRNAs may provide novel targets for therapeutic intervention and patentable discoveries may emerge. Although this application focuses on adipose tissue, we intend in the longer term to establish if miRNAs are also programmed in readily accessible tissues such as white blood cells with potential utility as biomarkers of disease risk that would indicate the need for lifestyle change or other intervention.
The lead researchers are actively engaged with the commercial pharmaceutical sector (including Unilever, Astra Zeneca and Abbott Laboratories) through joint research projects and studentships. The proposed research will inform and benefit this sector through access to new knowledge, technology development and databases. Thus in the longer term we foresee opportunities for commercialization of both diagnostics (identifying individuals at risk of metabolic disease as a consequence of early life nutrition) and therapeutics (targeting specific miRNAs whose programmed expression contributes to adverse metabolic phenotype). Thus the proposed research has potential to enhance the knowledge economy and economic competitiveness of the UK.
The research also has high relevance to the public sector, with potential to inform policy making with regard to advice on nutrition and healthy ageing, by strengthening the evidence base concerning relationships between nutrition during pregnancy and long-term health of offspring. The research is also readily accessible to the general public, because of its immediate relevance to improving health and well being and enhancing quality of life. The research therefore provides an excellent vehicle for increasing public engagement and understanding.