Origins of Diet-Induced Circadian Reprogramming and Plasticity

饮食引起的昼夜节律重编程和可塑性的起源

• 批准号: 10412989
• 负责人: Kristin Eckel Mahan
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10412989
• 关键词: ARNTL gene; Address; Antidiabetic Drugs; Architecture; Automobile Driving; Binding; Biochemical; Biochemistry; Bioinformatics; Biological Process; Body Temperature; Brain; Cells; Chromatin; Circadian Dysregulation; Circadian desynchrony; Complex; DNA; Data; Diet; Diet and Nutrition; Eating; Energy Intake; Fatty acid glycerol esters; Food; Gene Expression; Glucose Clamp; Goals; Hepatic; High Fat Diet; Homeostasis; Hormone secretion; Hour; Human; Impairment; Insulin; Insulin Receptor; Insulin Resistance; Intake; Knockout Mice; Knowledge; Light; Link; Liver; Mammals; Mass Spectrum Analysis; Mediating; Metabolic Control; Metabolic Diseases; Metabolism; Modeling; Mus; Nutrient; Obesity; Organ; PPAR gamma; Pacemakers; Patients; Periodicity; Peripheral; Phase; Planet Earth; Property; Proteins; Research; Risk; Rodent; Rodent Model; Seminal; Sleep; Techniques; Testing; Thiazolidinediones; Time; Tissues; Transcript; Transcription Coactivator; base; chromosome conformation capture; circadian; circadian pacemaker; design; detection of nutrient; dietary; epidemiology study; experimental study; feeding; innovation; insulin sensitivity; insulin sensitizing drugs; insulin signaling; nutrition; prevent; recruit

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.

人类适应地球自转产生的一天 24 小时。这种内部驱动的 24 小时（或者， “昼夜节律”）哺乳动物的适应产生睡眠、食物摄入、体温和激素的节律 分泌等生物过程。生物钟存在于所有细胞中，并受到以下因素的严重影响： zeitgebers（或“时间给予者”），例如食物和光。流行病学研究表明，环境或 遗传引起的生物钟扰乱导致代谢疾病，部分原因是生物钟失调 大脑的中央时钟和外围时钟。营养挑战，例如高脂肪饮食喂养，可以 以一种与大脑错位的方式重新编程肝脏生物钟。本次实验 该提案旨在检验以下假设：高脂肪饮食引起的昼夜节律重新编程是 这是通过以胰岛素依赖性方式不当招募昼夜节律蛋白 BMAL1 来实现的。 高脂肪饮食会在肝脏中长期产生胰岛素抵抗，将用于解决 肝重编程的潜在机制。特别是，我们将研究定位和染色体 在高脂肪喂养的条件下，招募关键的昼夜节律转录激活剂 BMAL1 蛋白。 BMAL1 蛋白对于细胞 24 小时节律是必需的，但在高脂肪饮食喂养下，它会被招募 与 DNA 不相适应，改变靶基因表达的 24 小时节律以及随后的昼夜节律 在肝脏中代谢。这种招募中断的机制尚不清楚，但我们 初步数据表明 BMAL1 招募的改变可能是肝脏胰岛素抵抗的结果，因为 通过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。其次，胰岛素信号传导是肝脏昼夜节律的主要驱动因素的假设 重编程将通过使用胰岛素抵抗啮齿动物模型以及一类 胰岛素增敏药物。这些实验将在很大程度上依赖于生物化学和生物信息学方法。 缺乏胰岛素受体（完全肝胰岛素抵抗模型）的啮齿动物将在 缺乏高脂肪喂养会导致 BMAL1 募集变化以及染色体结构变化 BMAL1 目标 DNA。此外，使用胰岛素增敏药物噻唑烷二酮类药物， 人类常用的方法将确定高脂肪饮食引起的昼夜节律重新编程是否是胰岛素- 依赖。总的来说，这些模型将揭示肝脏胰岛素抵抗是否必要或充分 用于饮食引起的肝脏昼夜节律重新编程。这些结果将对如何 其他胰岛素敏感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。

项目成果

Temporal and spatial metabolite dynamics impart control in adipogenesis.

• DOI: 10.1083/jcb.202210021
• 发表时间: 2022-12-05
• 期刊: The Journal of cell biology

Energy intake at the intersection of the clock and ageing.

• DOI: 10.1038/s41574-022-00791-3
• 发表时间: 2023-02
• 期刊: Nature reviews. Endocrinology

Hepatic circadian and differentiation factors control liver susceptibility for fatty liver disease and tumorigenesis.

• DOI: 10.1096/fj.202101398r
• 发表时间: 2022-09
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Atlas of Circadian Metabolism Reveals System-wide Coordination and Communication between Clocks.

昼夜主义代谢的地图集揭示了时钟之间全系统的协调和通信。

• DOI: 10.1016/j.cell.2018.08.042
• 发表时间: 2018-09-06
• 期刊: Cell
• 影响因子: 64.5
• 作者: Dyar KA;Lutter D;Artati A;Ceglia NJ;Liu Y;Armenta D;Jastroch M;Schneider S;de Mateo S;Cervantes M;Abbondante S;Tognini P;Orozco-Solis R;Kinouchi K;Wang C;Swerdloff R;Nadeef S;Masri S;Magistretti P;Orlando V;Borrelli E;Uhlenhaut NH;Baldi P;Adamski J;Tschöp MH;Eckel-Mahan K;Sassone-Corsi P
• 通讯作者: Sassone-Corsi P

Circadian Rhythms of the Hypothalamus: From Function to Physiology.

• DOI: 10.3390/clockssleep3010012
• 发表时间: 2021-02-25
• 期刊: Clocks & sleep
• 影响因子: 3.1
• 作者: Van Drunen R;Eckel-Mahan K
• 通讯作者: Eckel-Mahan K