Origins of Diet-Induced Circadian Reprogramming and Plasticity

人类适应地球自转产生的24小时一天。这是内部驱动的24小时(或， 哺乳动物的适应在睡眠、食物摄取、体温和激素方面产生节律性。 分泌物，以及其他生物过程。生物钟存在于所有细胞中，并受到 诸如食物和光线等时代因素(或“时间给予者”)。流行病学研究表明，环境或 基因诱导的生物钟紊乱导致代谢性疾病，部分原因是错位 大脑中的中央时钟和外围时钟。营养挑战，如高脂肪饮食喂养，可以 对肝脏生物钟进行重新编程，使其与大脑发生错位。这方面的实验 旨在验证高脂肪饮食诱导的昼夜节律重新编程是 这是通过以胰岛素依赖的方式不当招募昼夜节律蛋白BMAL1来实现的。 高脂肪饮食会长期在肝脏产生胰岛素抵抗，这将被用来解决 肝脏重编程的潜在机制。特别是，我们将研究定位和染色体 在高脂肪饲养条件下，关键的昼夜节律转录激活因子BMAL1蛋白的招募。 BMal1蛋白是细胞24小时节律性所必需的，但在高脂肪饲料喂养下，它被招募 不适当地与DNA结合，改变靶基因表达的24小时节律性和随后的昼夜节律 肝脏的新陈代谢。这一中断招聘背后的机制尚不清楚，但我们的 初步数据显示，BMAL1募集改变可能是肝脏胰岛素抵抗的结果，因为 应用抗糖尿病药物可恢复BMal1染色质募集和靶基因表达 噻唑烷二酮类化合物。其次，假设胰岛素信号是肝脏昼夜节律的主要驱动因素 重新编程将通过使用胰岛素抵抗啮齿动物模型的组合以及一类 胰岛素增敏药物。这些实验将在很大程度上依赖于生化和生物信息学方法。 缺乏胰岛素受体的啮齿动物(一种完全的肝脏胰岛素抵抗模型)将在 由于BMAL1募集和染色体结构的改变，没有高脂肪喂养 在BMAL1靶DNA上。此外，给予胰岛素增敏药物噻唑烷二酮类药物， 将决定高脂饮食诱导的昼夜节律重编程是否是胰岛素- 依附的。总的来说，这些模型将揭示肝脏胰岛素抵抗是必要的还是充分的。 用于在肝脏中进行饮食诱导的昼夜节律重新编程。这些结果将对如何 其他对胰岛素敏感的组织对饮食的反应以及饮食控制代谢稳态的程度 通过外周生物钟和中枢生物钟的同步。

Humans adapt to the 24-hour day produced by the earth rotating on its axis. This internally-driven 24-hour (or, “circadian”) adaptation in mammals produces rhythmicity in sleep, food intake, body temperature, and hormone secretion, among other biological processes. The circadian clock exists in all cells and is heavily influenced by zeitgebers (or, “time-givers”) such as food and light. Epidemiological studies reveal that environmentally- or genetically-induced perturbation of our circadian clock leads to metabolic disease, in part by misaligning the central clock in the brain with peripheral clocks. Nutrient challenge, such as high fat diet feeding, can reprogram the liver circadian clock in a manner that misaligns it from the brain. The experiments of this proposal are designed to test the hypothesis that high fat diet-induced circadian reprogramming is accomplished by improper recruitment of the circadian protein BMAL1, in an insulin-dependent manner. A high fat diet, which produces insulin resistance in the liver long term, will be used to address the mechanisms underlying hepatic reprogramming. In particular, we will study the localization and chromosomal recruitment of a key circadian transcriptional activator, the BMAL1 protein, under conditions of high fat feeding. BMAL1 protein is necessary for cellular 24-hour rhythmicity but under high fat diet feeding, it gets recruited inappropriately to DNA, altering 24-hour rhythmicity in target gene expression and subsequent circadian metabolism in the liver. The mechanisms underlying this disrupted recruitment are not known but our preliminary data suggest that altered BMAL1 recruitment may be a result of hepatic insulin resistance, as BMAL1 chromatin recruitment and target gene expression are restored by the application of the anti-diabetic thiazolidinediones. Secondly, the hypothesis that insulin signaling is the primary driver of hepatic circadian reprogramming will be tested by using a combination of insulin resistant rodent models as well as by a class of insulin-sensitizing drugs. These experiments will rely heavily on biochemical and bioinformatics approaches. Rodents which lack the insulin receptor (a model of complete hepatic insulin resistance) will be analyzed in the absence of high fat feeding for changes in BMAL1 recruitment as well as changes in chromosomal architecture at BMAL1 target DNA. In addition, administration of the insulin-sensitizing drugs, the Thiazolidinediones, commonly used in humans will determine whether high fat diet-induced circadian reprogramming is insulin- dependent. Collectively, these models will reveal whether hepatic insulin resistance is necessary or sufficient for diet-induced circadian reprogramming in the liver. These results will have important implications for how other insulin-sensitive tissues respond to diet and the extent to which diet may control metabolic homeostasis through synchrony of peripheral and central circadian clocks.