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

肥胖和相关疾病，包括2型糖尿病和心血管疾病，是英国和世界许多其他地区的主要健康问题。2004年，超过20%的英国成年人被归类为肥胖，到2050年，这一比例将超过50%，除非目前的趋势可以停止。据估计，2007年，与肥胖有关的问题花费了NHS约10亿英镑，预计到2050年将增加到近100亿英镑。真正的经济和社会成本要大得多。这些代谢健康问题通常归因于不良饮食和运动不足的综合影响。然而，人们也清楚地看到，不良的代谢健康可以从一代人到下一代人得到加强。这部分是由于遗传因素，部分是由于早期生活经历的环境。在子宫内和哺乳期的整个关键生长期，婴儿所经历的环境受到母亲健康状况和习惯的严重影响。母亲的饮食（以及吸烟和饮酒等因素）、母亲肥胖和妊娠期糖尿病可能对其后代的健康产生终身影响。然而，这些遗传和环境因素如何影响生命早期的生长却知之甚少。除了体型，我们还需要考虑在生命早期发育过程中形成的瘦肉（主要是肌肉）和脂肪组织比例的变化。我们一直在研究一组对生命早期发育有很大影响的基因，这些基因可能对环境因素（如母亲的饮食）异常敏感。其中两个基因，Dlk1和Grb10，以相反的方向影响身体大小和瘦：脂肪比例。Dlk1促进生长，包括出生时的大小，以及以后生活中脂肪组织的积累。相反，Grb10限制了生命早期的生长，并限制了以后脂肪的积累。使用小鼠遗传学，我们的目标是测试这些基因在生命早期建立瘦肉：脂肪比例的想法。我们将确定Dlk 1和Grb 10如何在细胞和分子水平上起作用。一组实验将使我们能够确定它们在脂肪组织发育中的作用。另一组实验将集中在它们在肌肉发育中的作用。我们将测试每个基因对成年后脂肪沉积的影响，当小鼠受到高脂肪饮食的挑战时。总之，这些实验将告诉我们这些基因如何通过影响生命早期的正常生长过程来影响终身健康。此外，我们将测试我们的想法，这两个基因的行为是对立的，推动和拉动身体的大小和比例在相反的方向。这将使我们能够确定参与这些重要过程的其他关键基因。

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.