Origins of Diet-Induced Circadian Reprogramming and Plasticity

人类适应了地球自转产生的24小时一天。这种内部驱动的24小时（或， 在哺乳动物中，生物钟（“昼夜节律”）适应产生睡眠、食物摄入、体温和激素的节律性。 分泌，以及其他生物过程。生物钟存在于所有细胞中，并受到以下因素的严重影响： 时间给予者（zeitgebers），如食物和光线。流行病学研究表明，环境-或 遗传引起的生物钟干扰会导致代谢疾病，部分原因是由于生物钟失调 大脑的中央时钟和外围时钟。营养挑战，如高脂肪饮食喂养，可以 重新编程肝脏的生物钟，使其与大脑不一致。这个实验 这些建议旨在检验高脂肪饮食诱导的昼夜节律重编程是 通过以胰岛素依赖的方式不适当地募集昼夜节律蛋白BMAL 1来完成。 高脂肪饮食会长期在肝脏中产生胰岛素抵抗， 肝重编程的潜在机制。特别是，我们将研究定位和染色体 在高脂喂养条件下，募集关键的昼夜节律转录激活因子BMAL 1蛋白。 BMAL 1蛋白是细胞24小时节律所必需的，但在高脂饮食喂养下，它会被招募 与DNA不适当，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。这种中断招募的机制尚不清楚，但我们的研究表明， 初步数据表明，BMAL 1募集的改变可能是肝脏胰岛素抵抗的结果， BMAL 1染色质募集和靶基因表达通过应用抗糖尿病药物而恢复 噻唑烷二酮类。其次，胰岛素信号传导是肝脏昼夜节律的主要驱动力的假设 将通过使用胰岛素抗性啮齿动物模型的组合以及通过一类 胰岛素增敏药物这些实验将严重依赖于生物化学和生物信息学方法。 缺乏胰岛素受体的啮齿动物（一种完全肝胰岛素抵抗模型）将在 缺乏高脂肪喂养导致BMAL 1募集的变化以及染色体结构的变化 在BMAL 1靶DNA上。此外，胰岛素增敏药物噻唑烷二酮类， 将确定高脂肪饮食诱导的昼夜节律重编程是否是胰岛素- 依赖。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 饮食诱导的肝脏昼夜节律重编程。这些结果将对我们如何 其他胰岛素敏感组织对饮食和饮食控制代谢稳态的程度有反应 通过外周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.