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Aryl hydrocarbon receptor regulation of energy metabolism

芳烃受体对能量代谢的调节

基本信息

批准号：
9890473
负责人：
Shelley A Tischkau
金额：
$ 44.25万
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：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9890473
关键词：
ARNTL gene Adipocytes Adipose tissue Affect Agonist Animals Aryl Hydrocarbon Receptor Behavior Blood Glucose Body Burden Body Composition Chromatin Chronic Chronic Disease Chronically Ill Chronotherapy Circadian Dysregulation Circadian Rhythms Curcumin Data Detection Development Diabetes Mellitus Diabetic mouse Diet Dioxins Dyslipidemias Eating Elements Energy Metabolism Exposure to Fasting Fatty acid glycerol esters Flavonoids Foundations Genes Genetic Transcription Goals Growth Healthcare Hepatic High Fat Diet Homeostasis Human Hypertension In Vitro Industrialization Insulin Insulin Resistance Life Expectancy Ligands Link Lipase Lipolysis Liver Luciferases Malignant Neoplasms Measures Mediating Metabolic Metabolic Diseases Metabolic syndrome Metabolism Modernization Molecular Mus Mutagenesis Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity associated disease Organ Organism Periodicity Pharmaceutical Preparations Phase Population Precipitating Factors Receptor Activation Regulation Reporting Repression Response Elements Rest Risk Science Signal Transduction Sleep Societies Stains Structure System Testing Time Tissues Toxic Environmental Substances Training Transcription Coactivator Transcription Process Triglycerides Weight Gain Wild Type Mouse Xenobiotics adipokines anthropogenesis aryl hydrocarbon receptor ligand base brain tissue career preparation circadian circadian behavioral rhythms circadian pacemaker combat cytokine dimer environmental chemical exposed human population feeding food surveillance glucose tolerance graduate student improved in vivo innovation insight insulin sensitivity insulin tolerance lipid biosynthesis lipophilicity metabolic rate mutant new therapeutic target novel novel therapeutics pandemic disease promoter response sterol esterase targeted treatment transcription factor translational study uncoupling protein 1 undergraduate student

项目摘要

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.

代谢综合征和糖尿病是现代社会的流行病。身体负荷增加和升高的人某些亲脂性异生物质如二恶英增加了2型糖尿病和代谢综合征的风险。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，即昼夜节律的破坏，特别是中枢神经系统的去极化，与代谢重要器官中的那些时钟不同，发生在长期AhR激活之后。代谢综合征发生在昼夜节律钟被打乱的小鼠中，糖尿病小鼠在昼夜节律慢性AhR激活导致肝脏和脂肪组织中的节律的类似破坏。这因此，一项提案试图将代谢综合征的发展与昼夜节律的长期AhR激活联系起来时钟中断由于许多AhR激动剂在脂肪中积累，因此该建议集中于脂肪中的节律破坏，组织作为代谢性疾病发展的促发因素。我们假设AhR的激活直接破坏了脂肪组织中的分子生物钟，脂肪组织;代谢综合征的发展后，时钟中断。最后，我们假设保护的节律性将减轻AhR激活对代谢参数的不利影响。该提案结合检查全身代谢参数和行为昼夜节律的方法，以及专注于AhR介导的代谢基因的抑制机制，由昼夜节律钟调节。具体目的探讨AhR激活状态对SCN和脂肪组织节律的影响，并建立基础理论。 AhR激活对这两个振荡器系统的影响的差异。目的I探索行为昼夜节律使用芳烃受体缺陷小鼠（AhRKO）对AhR活化状态的差异的节律和响应，具有AhR组成型激活的小鼠（CA-AhR），和用AhR激动剂处理的野生型小鼠。Aim II探索 AhR介导的脂解基因节律破坏的分子机制，这是已知的靶点，生物钟转录因子Clock和Bmal 1，重点是AhR和E-box之间的相互作用，介导的转录该项目为本科生和研究生提供了一个培训框架，为生物医学科学的职业生涯做准备。该提案强调了一种新颖的异生素作用机制在代谢综合征的发展，并提供了洞察的潜力，时间疗法作为一种治疗糖尿病和代谢综合征。