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Circadian Clock Disruption: A Mechanism for Dioxin-induced Metabolic Syndrome

昼夜节律紊乱：二恶英诱发代谢综合征的机制

基本信息

批准号：
8391750
负责人：
Shelley A Tischkau
金额：
$ 31.76万
依托单位：
SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8391750
关键词：
Affect Agonist Animals Aryl Hydrocarbon Receptor Attenuated Bioluminescence Body Burden Boxing Brain Chemicals Cholesterol Chromatin Chronotherapy Circadian Rhythms Complex Cyclic AMP Response Element Data Data Aggregation Development Diabetes Mellitus Diabetic mouse Diet Dioxins Elements Epidemiologic Studies Exposure to Fatty acid glycerol esters GLUT4 gene Gene Expression Genes Genetic Transcription Glucokinase Glucose Glucose Transporter Human Hyperglycemia Hyperlipidemia Immunoblotting In Vitro Incidence Industrial Waste Insulin Insulin Resistance Leptin Life Light Link Liver Luciferases Measures Mediating Metabolic Metabolic syndrome Molecular Mus Mutagenesis Non-Insulin-Dependent Diabetes Mellitus Pattern Periodicity Peripheral Peroxisome Proliferator-Activated Receptors Population Receptor Activation Receptor Signaling Regulation Reporting Repression Response Elements Risk Risk Factors Sleep Slice Societies Stimulus System Tetrachlorodibenzodioxin Time Triglycerides Waste Products Wild Type Mouse World Health Organization Xenobiotics anthropogenesis blood glucose regulation circadian behavioral rhythms circadian pacemaker dimer environmental chemical exposed human population feeding gene function glucose metabolism glucose sensor insight lipid metabolism man mutant novel pandemic disease promoter public health relevance receptor response restoration suprachiasmatic nucleus

项目摘要

DESCRIPTION (provided by applicant): Metabolic syndrome and diabetes are pandemic in modern society. Epidemiological studies indicate increased incidence of insulin resistance and type 2 diabetes in humans with elevated body burden of certain lipophilic xenobiotics such as dioxins. These anthropogenic substances exert their effects through activation of aryl hyrdrocarbon receptor (AhR). Preliminary data present a compelling argument that disruption of circadian rhythmicity, particularly desynchronization of clocks located in the brain and liver, occurs subsequent to long-term AhR activation. Metabolic syndrome develops in mice that have a disrupted circadian clock, and diabetic mice display marked alterations in circadian rhythms. This proposal thus seeks to link the development of metabolic syndrome in response to long term AhR activation to circadian clock disruption. We hypothesize that AhR activation directly disrupts the molecular circadian clock in the liver and creates desynchrony between clocks in the brain and the liver; metabolic syndrome develops subsequent to clock disruption. Finally, we hypothesize that restoration of rhythmicity will alleviate the detrimental effects of AhR activation on metabolic parameters. The proposal combines approaches that examine systemic metabolic parameters and behavioral circadian rhythms and molecular studies that focus on mechanisms of AhR-mediated repression of circadian clock gene expression. Specific aims I and II explore effects of AhR activation state on SCN and liver rhythms, respectively, and establishes fundamental differences in the effects of AhR activation on these two oscillator systems. Aim I explores behavioral circadian rhythms and SCN responses to differences in AhR activation state using aryl hydrocarbon receptor-deficient mice (AhRKO), mice with constitutive activation of AhR (CA-AhR), and wild-type mice treated with long-acting or short-acting AhR agonists. Aim II uses mPer2luc mice and real time bioluminescence to determine effects of AhR activation on the liver clock. Aim III explores molecular mechanisms of AhR-mediated disruption of clock gene function, with an emphasis on interactions between AhR and E-box-mediated transcription driven by the clock genes, Clock and Bmal1. Aim IV explores metabolic changes associated with clock gene disruption after AhR activation and the effects of reversing these disruptions. The proposal highlights a novel mechanism for xenobiotic action in the development of metabolic syndrome and provides insight into the potential for chronotherapy as a treatment for diabetes and metabolic syndrome.

描述（由申请人提供）：代谢综合征和糖尿病在现代社会中流行。流行病学研究表明，人体体内某些亲脂性异生物质（如二恶英）负荷增加，胰岛素抵抗和 2 型糖尿病的发病率会增加。这些人为物质通过激活芳基烃受体（AhR）发挥作用。初步数据提出了一个令人信服的论点，即昼夜节律的破坏，特别是位于大脑和肝脏的时钟不同步，发生在长期 AhR 激活之后。生物钟被破坏的小鼠会出现代谢综合征，而患有糖尿病的小鼠则表现出昼夜节律的显着改变。因此，该提案试图将长期 AhR 激活引起的代谢综合征的发展与生物钟破坏联系起来。我们假设 AhR 激活直接扰乱肝脏中的分子生物钟，并在大脑和肝脏的时钟之间造成不同步；生物钟紊乱后会出现代谢综合征。最后，我们假设节律性的恢复将减轻 AhR 激活对代谢参数的不利影响。该提案结合了检查全身代谢参数和行为昼夜节律的方法以及专注于 AhR 介导的生物钟基因表达抑制机制的分子研究。具体目标 I 和 II 分别探讨 AhR 激活状态对 SCN 和肝脏节律的影响，并确定 AhR 激活对这两个振荡系统的影响的根本差异。目标 I 使用芳烃受体缺陷型小鼠 (AhRKO)、AhR 组成型激活小鼠 (CA-AhR) 以及用长效或短效 AhR 激动剂治疗的野生型小鼠，探讨行为昼夜节律和 SCN 对 AhR 激活状态差异的反应。 Aim II 使用 mPer2luc 小鼠和实时生物发光来确定 AhR 激活对肝脏时钟的影响。 Aim III 探索 AhR 介导的时钟基因功能破坏的分子机制，重点是 AhR 和由时钟基因 Clock 和 Bmal1 驱动的 E-box 介导的转录之间的相互作用。 Aim IV 探讨了 AhR 激活后与时钟基因破坏相关的代谢变化以及逆转这些破坏的影响。该提案强调了异生物质在代谢综合征发生过程中的一种新机制，并深入了解了时间疗法作为糖尿病和代谢综合征治疗的潜力。

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）

Aryl hydrocarbon receptor deficiency protects mice from diet-induced adiposity and metabolic disorders through increased energy expenditure.

DOI：
10.1038/ijo.2015.63
发表时间：
2015-08
期刊：
International journal of obesity (2005)
影响因子：
0
作者：
Xu CX;Wang C;Zhang ZM;Jaeger CD;Krager SL;Bottum KM;Liu J;Liao DF;Tischkau SA
通讯作者：
Tischkau SA

Mechanisms of circadian clock interactions with aryl hydrocarbon receptor signalling.

昼夜节律与芳基烃受体信号传导相互作用的机制。