The role of circadian rhythm genes in the regulation of energy balance and substrate metabolism in muscle and liver

肥胖在全球范围内正以惊人的速度增长，随着印度和中国等发展中国家生活水平的提高，肥胖及其相关疾病糖尿病、心血管疾病和癌症的发病率将成为21世纪的主要健康问题。肥胖的流行似乎是由于遗传背景和环境变化之间的复杂相互作用，例如体力活动减少和高能量食物的可获得性和消耗量增加。大多数人体内过多的脂肪积累并不是几天或几周内就会发生的突发事件。肥胖实际上是在一段时间内潜移默化地发生的，本质上是日常能量平衡微小差异的累积结果。在人类和动物中，能量平衡受到体温、摄食行为和身体活动(睡眠-觉醒周期)的昼夜变化的影响。最近的研究已经确定，人体内的所有组织都有相同的基因来调节大脑的昼夜节律。同样清楚的是，这些基因在肌肉、肝脏和脂肪组织中的表达周期超过24小时，与它们在大脑中的表达方式相同。目前还不清楚的是，这些昼夜节律基因在多大程度上控制着能量代谢途径，如葡萄糖和脂肪的利用以及肝脏和肌肉中的储存。这笔赠款的目的是测试改变饮食、喂食时间和循环激素对肌肉和肝脏新陈代谢和基因表达的影响，以确定昼夜节律基因在多大程度上调节葡萄糖和脂肪的正常日常代谢，以及这些系统的失调是否会导致代谢性疾病。

Obesity is increasing at an alarming rate worldwide and as the standard of living increases in developing countries such as India and China, the incidence of obesity and its related diseases of diabetes, cardiovascular disease and cancer will become the major health problem of the 21st century. The epidemic of obesity appears to be due to a complex interaction between genetic background and changes in the environment such as reduced physical activity and increased availability and consumption of high energy food. The accumulation of excess body fat in most individuals is not a precipitous event that occurs over a few days or weeks. Obesity actually occurs insidiously over a period years and is essentially the cumulative result of small differences in daily energy balance. In humans and animals energy balance is subject to diurnal or day-night variations in body temperature, feeding behaviour and physical activity (sleep-wake cycles). Recent research has determined that all tissues in the body have the same genes that regulate circadian (daily) rhythms in the brain. It has also become clear that the expression of these gene cycles over 24 hours in muscle liver and fat tissue the same way that they do in the brain. What is not understood is the extent to which these circadian genes control energy metabolism pathways such as glucose and fat utilisation and storage in liver and muscle. The aim of this grant is to test the effects of changing diet, feeding times and circulating hormones on metabolism and gene expression in muscle and liver to determine the extent to which circadian rhythm genes regulate the normal diurnal metabolism of glucose and fat and whether dysregulation of these systems contributes to metabolic disease.