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

• 批准号: 8005041
• 负责人: Shelley A Tischkau
• 金额: $ 32.41万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8005041
• 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

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. PUBLIC HEALTH RELEVANCE: Human and animal populations are increasingly exposed to toxic environmental chemicals as a result of living in a heavily industrialized world. Human exposure to dioxins causes both sleep and metabolic disturbances, including increased risk of type II diabetes and metabolic syndrome. This proposal examines the novel hypothesis that dioxins exert their action through aryl hydrocarbon receptor-mediated uncoupling of homeostatic regulation of organismic circadian rhythms.

描述（申请人提供）：代谢综合征和糖尿病是现代社会的流行病。流行病学研究表明，随着某些亲脂性外源性物质（如二恶英）的体内负荷增加，胰岛素抵抗和2型糖尿病的发病率增加。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中的时钟的去同步化，发生在长期AhR激活之后。代谢综合征发生在昼夜节律紊乱的小鼠中，糖尿病小鼠的昼夜节律显示出明显的改变。因此，该提议试图将代谢综合征的发展与长期AhR激活和生物钟破坏联系起来。我们假设AhR激活直接破坏了肝脏中的分子生物钟，并在大脑和肝脏中的时钟之间产生了混乱;代谢综合征在时钟中断后发展。最后，我们假设恢复节律性将减轻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探索SCN和肝节律的AhR激活状态的影响，分别，并建立在AhR激活对这两个振荡器系统的影响的根本差异。目的我探索行为昼夜节律和SCN的反应，在AhR激活状态的差异，使用芳烃受体缺陷小鼠（AhRKO），小鼠组成性激活AhR（CA-AhR），和野生型小鼠治疗长效或短效AhR激动剂。目的II使用mPer 2luc小鼠和真实的时间生物发光来确定AhR激活对肝时钟的影响。目的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E-box介导的时钟基因Clock和Bmal 1驱动的转录之间的相互作用。目的IV探讨AhR激活后与时钟基因中断相关的代谢变化以及逆转这些中断的影响。该提案强调了代谢综合征发展中外源性作用的新机制，并提供了时间疗法作为糖尿病和代谢综合征治疗的潜力。 公共卫生相关性：由于生活在一个高度工业化的世界中，人类和动物群体越来越多地暴露于有毒的环境化学品。人类接触二恶英会导致睡眠和代谢紊乱，包括增加患II型糖尿病和代谢综合征的风险。该提案检验了一个新的假设，即二恶英通过芳烃受体介导的生物体昼夜节律稳态调节的解偶联发挥作用。