Imprinted gene expression in early life determines body composition and response to the obesogenic environment.

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 combined effects of poor diet and insufficient exercise. However, it has also become clear that poor metabolic health can be reinforced from one generation to the next. This is partly due to inherited factors and partly due to the environment experienced during early life. Throughout the critical growth periods in the womb and as suckling infants, babies experience an environment that is heavily influenced by the health status and habits of their mother. 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. However, how these genetic and environmental factors influence growth during early life is poorly understood. In addition to body size we need to consider changes in the proportions of lean (mainly muscle) and fat tissues that are laid down during early life development.

We have been studying a group of genes that have a strong influence on early life growth and may be unusually sensitive to environmental factors such as maternal diet. Two of these genes, Dlk1 and Grb10, influence body size and lean:fat proportions in opposite directions. Dlk1 promotes growth, including size at birth, and also the accumulation of fat tissue in later life. Conversely, Grb10 restricts growth in early life and limits the accumulation of fat later on. Using mouse genetics, we aim to test the idea that these genes act in early life to establish lean:adipose proportions. We will establish how Dlk1 and Grb10 act at the level of cells and molecules. One set of experiments will allow us to determine their actions in developing fat tissue. Another set of experiments will focus on their roles in muscle development. We will test the effects of each gene on fat deposition in adult life when mice are challenged with a high fat diet. Together, these experiments will tell us how these genes could affect life-long health by influencing normal growth processes during early life. In addition, we will test our idea that the two genes act antagonistically, pushing and pulling body size and proportions in opposite directions. This will allow us to identify other key genes involved in these important processes.

Obesity, or excessive expansion of white adipose tissue, is strongly correlated with metabolic diseases such as cardiovascular disease and type II diabetes. Whereas some individuals can maintain obesity with few metabolic consequences, in others it causes disease. This difference is due to the distribution of fat storage in the body, which in turn relates to adipocyte size and proliferation. Inter-individual variation in adipose tissue depot-distribution and expandability is determined during development, and there is evidence that the majority of adipose precursor cells are already present at birth. Skeletal muscle mass across the whole range of human variation is correlated with insulin sensitivity and glucose tolerance. There is strong evidence that both fat distribution and skeletal mass are highly heritable traits. Despite this, the genetic/developmental processes underpinning human variation in body composition is poorly understood.
Genetic manipulation of imprinted gene expression in mice has demonstrated that these genes functionally link body composition to energy homeostasis. Such associations between lean:adipose mass are also observed in human patients with imprinted growth disorders such as Silver Russell Syndrome and Temple Syndrome, who have have altered body compostion in early life followed by truncal obesity. However, the molecular pathways modulated by this important class of developmentally regulated genes on body composition have been relatively understudied. We will use two mouse models (deletions of the imprinted genes Dlk1 and Grb10) that shift lean:adipose mass in opposite directions, to interrogate the molecular mechanisms that underlie the early life acquisition of fat and muscle. We will combine these imprinted gene deletions with lineage tracing tools and dietary manipulation to understand the complex interplay between genetics and the environment, and to ultimately understand human variation in the susceptibility to metabolic disease.

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 2014-2019, 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 genetics underlying human variation in body composition, 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, at least in part, from developmental processes occurring during early life. However, findings made in the model systems 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 in the model systems 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 establishment of the adult body plan could be investigated as potential therapeutic targets. There is also potential to influence health through the adoption of simple practices such as changes in 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. There are already major screens for genetic markers underlying human variation in body composition, and some of these are beginning to consider parental-origin effects (for example Horikoshi, Nature Genetics 2016). Our data will complement such population studies and relate genetic variations to biological mechanism and ultimately help us to understand metabolic disease. 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.