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

基本信息

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
项目类别：
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

项目摘要

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.

人类适应地球在其轴上旋转的24小时一天。这个内部驱动的24小时（或 “昼夜节律”）适应哺乳动物的睡眠，食物摄入量，体温和马的节奏性分泌，除其他生物过程。昼夜节律都存在于所有细胞中，并受到很大的影响 Zeitgebers（或“时机”），例如食物和光。流行病学研究表明，环境或循环引起的昼夜节律扰动导致代谢疾病，部分原因是带有外围钟的大脑中心时钟。营养挑战，例如高脂饮食喂养，可以重新编程肝脏昼夜节律的时钟，使其从大脑中错过。实验的实验建议旨在检验以下假设：高脂饮食引起的昼夜节律是通过以胰岛素依赖性方式募集昼夜节律蛋白BMAL1的募集来实现。长期在肝脏中产生胰岛素抵抗的高脂饮食将用于解决肝脏重编程的基础机制。特别是，我们将研究定位和染色体在高脂肪进食的条件下募集关键的昼夜节律转录激活剂BMAL1蛋白。 BMAL1蛋白对于细胞24小时的节奏性是必需的，但在高脂饮食喂养下，它被招募不恰当地到DNA，改变靶基因表达和随后的昼夜节律的24小时节奏性肝脏中的代谢。这种破坏招聘的机制尚不清楚，但我们初步数据表明，BMAL1募集的改变可能是肝胰岛素抵抗的结果，如 BMAL1染色质募集和靶基因表达通过抗糖尿病的应用恢复噻唑烷二酮。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重新编程将通过使用胰岛素耐药啮齿动物模型以及一类的组合来测试胰岛素敏化药物。这些实验将严重依赖生化和生物信息学方法。缺乏胰岛素受体的啮齿动物（一种完全肝胰岛素抵抗的模型）将在没有高脂肪供给BMAL1募集的变化以及染色体结构的变化在BMAL1靶DNA处。此外，胰岛素敏化药物的给药，噻唑烷二酮，人类通常使用的将确定高脂饮食诱导的昼夜节律是否是胰岛素依赖。总的来说，这些模型将揭示肝胰岛素抵抗是必要的还是足够的用于饮食引起的昼夜节律重编程。这些结果将对如何其他对胰岛素敏感的时机对饮食以及饮食可能控制代谢稳态的程度有反应通过外围和中央昼夜节律时钟的同步。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
作者：
通讯作者：

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
影响因子：
0
作者：
通讯作者：

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

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

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