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

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，在体内负荷增加的某些亲脂性异物如二恶英的人类中，胰岛素抵抗和2型糖尿病的发生率增加。这些人为物质通过激活芳基氢碳受体(AhR)发挥作用。初步数据提出了一个令人信服的论点，即昼夜节律性的破坏，特别是位于大脑和肝脏的时钟的去同步，发生在长期的AhR激活之后。代谢综合征发生在生物钟被打乱的小鼠身上，糖尿病小鼠表现出明显的昼夜节律变化。因此，这一建议试图将长期激活AhR引起的代谢综合征的发展与生物钟紊乱联系起来。我们假设AhR的激活直接扰乱了肝脏的分子生物钟，并在大脑和肝脏的时钟之间造成了去同步；代谢综合征发生在时钟中断之后。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。该提案结合了检测系统代谢参数和行为昼夜节律的方法，以及专注于AhR介导的抑制昼夜节律基因表达的机制的分子研究。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，并建立AhR激活对这两个振荡器系统影响的根本区别。目的研究芳香烃受体缺陷小鼠(AhRKO)、结构性激活AhR小鼠(CA-AhR)和长效或短效AhR激动剂处理的野生型小鼠的行为昼夜节律和SCN对AhR激活状态差异的反应。目的利用mPer2luc小鼠和实时生物发光技术研究AhR激活对肝脏生物钟的影响。目的探讨AhR干扰Clock基因功能的分子机制，重点探讨AhR与由Clock基因、Clock和BMal1驱动的E-box介导的转录之间的相互作用。目的探讨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效果。该提案强调了异物作用在代谢综合征发展中的一种新机制，并提供了对时间疗法作为糖尿病和代谢综合征治疗的潜力的洞察。 公共卫生相关性：由于生活在一个高度工业化的世界，人类和动物人口越来越多地暴露在有毒环境化学品中。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。这项建议检验了新的假设，即二恶英通过芳香烃受体介导的生物体昼夜节律的动态平衡调节解偶联来发挥作用。

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.