Mechanisms underlying developmental programming of lifelong health

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的"西方"饮食和运动不足对个人的直接影响。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。这是因为在子宫内和哺乳期，即生命早期的关键生长期，婴儿经历的环境受到母亲健康状况和习惯的严重影响。特别是，母亲的饮食（以及吸烟和饮酒等因素），母亲肥胖和妊娠糖尿病可能对其后代的健康产生终身影响。换句话说，当我们习惯于“你吃什么就是什么”的想法时，我们也应该注意“你是你母亲吃什么”的想法。我们的研究旨在找出影响早期生命生长的因素，特别是母亲饮食不良，如何影响成年后的健康。人们认为，发育中的后代是由他们所经历的环境"编程"的，这个过程涉及打开和关闭控制生长、脂肪组织发育以及身体储存和使用能量等过程的基因。我们的目标是确定受发育编程影响的后代中的关键基因。为了做到这一点，我们正在研究一种名为Grb10的基因被破坏的小鼠。这些小鼠出生时体型较大，成年后具有良好的代谢健康特征，包括低脂肪水平和餐后使用葡萄糖的能力增强。该基因将早期生长与成年健康联系起来的事实使其成为参与代谢编程的基因之一。我们将通过发现这些小鼠的"抗糖尿病"特征是否可以保护它们免受不良母体饮食对健康的不利影响来测试这是否是真的。我们还将使用这些小鼠来揭示作为编程过程的一部分而打开或关闭的其他基因。通过识别参与发育编程的基因，并找出它们的活动何时以及在身体的哪些部位发生变化，我们将找到未来改善人类健康的新方法。这可能包括开发测试来识别在以后的生活中常见健康问题风险增加的人，改善怀孕期间的饮食建议或饮食补充，或开发改变发育编程基因活性的药物。

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.