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，在某些亲脂性外源性药物（如二恶英）的身体负荷升高的人群中，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）来发挥作用。初步数据提供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不同步，发生在长期AhR激活之后。生物钟紊乱的小鼠会出现代谢综合征，糖尿病小鼠的昼夜节律也会出现明显的改变。因此，该建议试图将代谢综合征的发展与长期AhR激活与生物钟中断联系起来。我们假设AhR的激活直接破坏了肝脏中的分子生物钟，并造成了大脑和肝脏时钟之间的不同步；代谢综合征是生物钟紊乱的结果。最后，我们假设节律性的恢复将减轻AhR激活对代谢参数的有害影响。该提案结合了检查全身代谢参数和行为昼夜节律的方法，以及关注ahr介导的生物钟基因表达抑制机制的分子研究。具体目的I和II分别探讨了AhR激活状态对SCN和肝脏节律的影响，并建立了AhR激活对这两个振荡系统影响的根本差异。目的1利用芳烃受体缺陷小鼠（AhRKO）、AhR组成型激活小鼠（CA-AhR）和使用长效或短效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探讨了AhR介导的时钟基因功能破坏的分子机制，重点研究了AhR与时钟基因、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。该建议强调了代谢综合征发展过程中外源作用的新机制，并为时间疗法作为糖尿病和代谢综合征治疗的潜力提供了见解。

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.