The role of stress response and circadian genes in the link between excess lipid and muscle insulin resistance

肥胖及其相关的心脏病、胰岛素作用降低、脂肪肝和2型糖尿病等病症在全球范围内正以惊人的速度增加。这些疾病的流行似乎是由于遗传背景和环境变化之间的相互作用，例如减少体力活动和增加高能量食物的供应和消费。基因和环境之间的关系非常复杂，但似乎很明显，增加高脂肪食物的摄入会导致身体组织积累多余的脂肪。这干扰了胰岛素激素控制身体葡萄糖利用的方式，尽管这是如何发生的还没有完全确定。这项拨款申请将测试两种可能的机制，可以帮助解释增加膳食脂肪摄入量和减少肌肉中胰岛素作用之间的联系。使用微阵列检测正常和胰岛素抵抗肌肉中基因的活性，我们已经确定了两组可能与脂肪如何导致胰岛素抵抗有关的基因。一组基因通常与压力有关，我们将确定脂肪是否直接控制这些基因，或者脂肪是否会增加其他压力因素，从而增加这些基因的活性。然后，我们将使用新的基因治疗技术，看看这些基因是否会导致实验动物肌肉中的胰岛素抵抗。第二组基因与调节身体日常周期的机制有关，如睡眠-觉醒周期，血压和饮食行为。我们将在24小时内检查这些基因在正常动物和胰岛素抵抗动物肌肉中的活性，以确定这些基因周期的破坏是否有助于胰岛素抵抗。然后，我们将进行实验，以确定这些基因控制的过程。这项资助的成功结果将决定这些基因组是否可以靶向治疗肌肉中脂质诱导的胰岛素抵抗。

Obesity and its associated conditions of heart disease, reduced insulin action, fatty liver and type 2 diabetes are increasing at an alarming rate worldwide. The epidemic of these conditions appears to be due to an interaction between genetic background and changes in the environment such as reduced physical activity and increased availability and consumption of high energy food. The relationship between genes and environment is very complex but it seems clear that increased intake of high fat foods can cause body tissues to accumulate excess fat. This interferes with the way that the hormone insulin controls body glucose utilisation although how this happens has not been fully defined. This grant application will test two possible mechanisms that could help explain the link between increased dietary fat intake and decreased insulin action in muscle. Using microarrays to examine the activity of genes in normal and insulin resistant muscle, we have identified two groups of genes that may be involved in how fat causes insulin resistance. One group of genes is normally associated with stress and we will determine if fats control these genes directly or if fats increase other stress factors which increase the activity of these genes. We will then use novel gene therapy techniques to see if these genes cause insulin resistance in muscle of experimental animals. The second group of genes is related to the mechanisms which regulate daily cycles in the body such as sleep-wake cycles, blood pressure, and eating behaviour. We will examine the activity of these genes over a 24 hour period in muscle from normal animals and insulin resistant animals to determine if disruption of these gene cycles contributes to insulin resistance. We will then perform experiments to establish what processes these genes control. The successful outcome of this grant will determine if these groups of genes can be targeted to help treat lipid-induced insulin resistance in muscle.