Mechanisms underlying developmental programming of lifelong health

Obesity and related disorders, including type 2 diabetes and cardiovascular disease, are major health problems in the UK and many other parts of the world. Over 20% of UK adults were classed as obese in 2004 and this will reach over 50% by 2050 unless current trends can be halted. Obesity-related problems were estimated to cost the NHS around £1bn in 2007 and this is predicted to rise to almost £10bn by 2050. The true financial and societal costs are much greater. These metabolic health problems are generally attributed to the direct effects on individuals of poor "Western" diets and insufficient exercise. However, it has also become clear that poor metabolic health can be reinforced from one generation to the next. This is because during life in the womb and as suckling infants, the critical growth periods of early life, babies experience an environment that is heavily influenced by the health status and habits of their mother. In particular, a mother's diet (as well as factors such as smoking and alcohol consumption), maternal obesity and gestational diabetes can have life-long effects on the health of her offspring. In other words, while we are used to the idea that "you are what you eat", we should also pay attention to the idea that "you are what your mother ate".

Our research aims to find out how factors affecting growth during early life, particularly poor maternal diet, can influence health during adult life. It is thought that developing offspring are "programmed" by the environment they experience in a process that involves switching on and off genes that control processes such as growth, adipose tissue development and also the way the body stores and uses energy. We aim to identify the key genes in offspring that are affected by developmental programming. To do this we are studying mice in which one gene, called Grb10, is disrupted. These mice are large at birth and have favourable metabolic health characteristics during adult life, including low adipose levels and an enhanced ability to use glucose after a meal. The fact that this gene links early growth with adult health makes it a strong candidate as one of the genes involved in metabolic programming. We will test if this is true essentially by finding out whether the "anti-diabetic" profile of these mice can protect them from the adverse health effects of a poor maternal diet. We will also use these mice to reveal other genes switched on or off as part of the programming process.

By identifying the genes involved in developmental programming, and finding out when and in which parts of the body their activity is altered, we will identify new ways to improve human health in the future. This could include the development of tests to identify people at increased risk of common health problems in later life, improvements in dietary advice or dietary supplementation during pregnancy, or the development of drugs that alter the activity of developmental programming genes.

Mother:offspring interactions during pregnancy and lactation are defining features of mammals. Poor maternal diet, maternal obesity and gestational diabetes directly influence offspring growth and lead to prevalent health problems including obesity, type 2 diabetes and cardiovascular disease. Developmental programming of offspring health is well recognised but the underlying mechanisms are poorly understood. Progress through human studies is hampered by the long time-scales involved and the obvious ethical barriers to experimental interventions. A number of useful animal models have been developed involving manipulation of offspring growth, typically through manipulation of maternal diet, but rapid further progress will require a genetic model of developmental programming. We have produced such a model using a knockout of the imprinted Grb10 gene. Grb10 knockout mice are large at birth and as adults are lean with enhanced insulin signalling and improved ability to clear a glucose load. Cross-fostering experiments allowed us to separate effects of Grb10 acting in offspring from those of maternal Grb10. Our findings indicate that Grb10 has evolved coadapted functions in mother and offspring in order to optimize offspring growth and physiology. These properties indicate a role for Grb10 as a developmental programming gene. In support of this, in recent studies of two different maternal dietary restriction models Grb10 was found to be up-regulated in the liver of affected offspring.

Here, we propose to directly test the role of Grb10 as a developmental programming gene by combining our genetic model with an established maternal dietary restriction model. This will be the first functional validation of a developmental programming gene. We will also use our combined model to identify further developmental programming genes as well as signature epigenetic changes (DNA methylation and histone modifications) associated with them.

The proposed research aligns with the MRC mission to support research that aims to improve human health. It is directly relevant to several objectives of the MRC Strategic Plan 2009-2014, specifically those of Research Priority Theme 2, Living a long and healthy life: i) Genetics and disease. Using genetics and biological indicators to understand predispositions to disease, and to target treatments to disease subtypes; ii) Life course perspective. Driving forward interdisciplinary research addressing health and wellbeing from childhood to older age; iii) Lifestyles affecting health. Determine the most effective strategies for tackling lifestyles that are detrimental to health; iv) Environment and health. Exploring the impacts of changes in our environment on health and wellbeing.

The work is essentially of a fundamental nature and will be carried out in a model organism. It has the aim of understanding the mechanisms involved in the process of developmental programming, which is directly relevant to some of the most important global health problems including obesity, type 2 diabetes and cardiovascular disease. Progress in human populations is made difficult by the long time-scales involved in studying a process that involves the effects on life-long health that result from conditions experienced during early life. However, findings made in the model system we have established could be rapidly assimilated by biomedical researchers and applied to human studies. For instance, genes that we identify to have altered regulation and/or epigenetic modifications in the model system could be investigated as potential markers of health risk in longitudinal studies of people. Genes and associated pathways identified to have a functional role in developmental programming could be investigated as potential therapeutic targets. There is also potential to influence health through the adoption of simple practices such as changes in maternal diet and dietary supplementation. Ultimately therefore, the research could lead to improvements in health and healthcare that would benefit the general public in and beyond the UK.

As the data emerge we will seek to extend our collaborations with researchers involved in the appropriate types of population study. This could lead to exploration of possible health benefits within the lifespan of the project or soon after its completion. Thus, translation of findings from our model system to developmental programming in humans, along with the development of early markers of health risks could commence within the next few years. The development of new interventions, including dietary advice and supplementation, or the development of drugs targeting effector molecules or pathways is likely to take considerably longer.