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

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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.