Aryl hydrocarbon receptor regulation of energy metabolism

代谢综合征和糖尿病是现代社会的流行病。人类的身体负担增加和增加 某些亲脂性外源物质，如二恶英，患2型糖尿病和代谢综合征的风险增加。这些 人为物质通过激活芳烃受体(AhR)发挥作用。初步数据 提出了一个令人信服的论点，即昼夜节律性的破坏，特别是中枢去同步化 来自代谢重要器官的时钟，发生在长期的AhR激活之后。新陈代谢 综合症发生在生物钟紊乱的小鼠身上，糖尿病小鼠表现出明显的 昼夜节律。慢性AhR的激活在肝脏和脂肪组织中引起类似的节律紊乱。这 因此，该提案试图将长期的AhR激活引起的代谢综合征的发展与昼夜节律联系起来。 时钟被打乱。因为许多血管紧张素转换酶激动剂在脂肪中积聚，所以这项建议侧重于脂肪的节律紊乱。 组织作为代谢性疾病发展的诱因。我们假设AhR直接激活 打乱脂肪组织的分子生物钟，使大脑和大脑的生物钟失去同步性 脂肪组织；代谢综合征是在生物钟被打乱之后发展起来的。最后，我们假设保护 节律性的改变将减轻AhR激活对代谢参数的不利影响。该提案结合了 检查系统代谢参数和行为昼夜节律的方法以及分子研究 重点研究AhR介导的代谢基因的抑制机制，这些基因受生物钟的调节。特定的 目的探讨AHR激活状态对SCN和脂肪组织节律的影响，为进一步研究AHR激活状态奠定基础 AhR激活对这两个振子系统影响的差异。目标I探索行为昼夜节律 芳烃受体缺陷小鼠(AhRKO)AhR激活状态的节律和对不同状态的反应 AhR结构性激活的小鼠(CA-AhR)，以及用AhR激动剂治疗的野生型小鼠。AIM II探索 AhR介导的脂解基因节律中断的分子机制，这是已知的靶点 生物钟转录因子Clock和BMal1，重点是AhR和E-box之间的相互作用。 中介转录。该项目为培养本科生和研究生提供了一个框架 为生物医学科学的职业生涯做准备。该提案强调了异种生物作用的一种新机制。 在代谢综合征的发展中的作用，并提供了对时间疗法作为一种 治疗糖尿病和代谢综合征。

Metabolic syndrome and diabetes are pandemic in modern society. Humans with increased and elevated body burden of certain lipophilic xenobiotics such as dioxins are at increased risk for type 2 diabetes and metabolic syndrome. These anthropogenic substances exert their effects through activation of aryl hydrocarbon receptor (AhR). Preliminary data present a compelling argument that disruption of circadian rhythmicity, particularly desynchronization of the central clock from those in metabolically important organs, 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. Chronic AhR activation causes a similar disruption in rhythms in liver and adipose tissue. This proposal thus seeks to link the development of metabolic syndrome in response to long-term AhR activation to circadian clock disruption. Because many AhR agonists accumulate in fat, this proposal focuses on rhythm disruption in adipose tissue as a precipitating factor in the development of metabolic disease. We hypothesize that AhR activation directly disrupts the molecular circadian clock in adipose tissue and creates desynchrony between the clock in the brain and adipose tissue; metabolic syndrome develops subsequent to clock disruption. Finally, we hypothesize that protection 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 metabolic genes that are regulated by the circadian clock. Specific aim I explores effects of AhR activation state on SCN and adipose tissue rhythms, and establishes fundamental differences in the effects of AhR activation on these two oscillator systems. Aim I explores behavioral circadian rhythms and 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 an AhR agonist. Aim II explores molecular mechanisms of AhR-mediated disruption of rhythms in lipolysis genes, which are known targets of the circadian clock transcription factors, Clock and Bmal1, with an emphasis on interactions between AhR and E-box- mediated transcription. The project provides a framework for training both undergraduate and graduate students in preparation for careers in the biomedical sciences. 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.