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.

在现代社会中，代谢综合征和糖尿病是大流行的。人类的身体负担增加和增加某些亲脂性异种生物（例如二恶英）的风险增加了2型糖尿病和代谢综合征。这些人为物质通过激活芳基烃受体（AHR）发挥其作用。初步数据提出了一个令人信服的论点，即昼夜节律的破坏，尤其是中央的不同步在长期AHR激活之后发生的代谢重要器官中的时钟。代谢综合征在昼夜节律中断的小鼠中发展，糖尿病小鼠显示出明显改变的小鼠昼夜节律。慢性AHR激活会导致肝脏和脂肪组织的节奏类似。这因此，提案试图将代谢综合征的发展与昼夜节律联系起来时钟破坏。因为许多AHR激动剂会积聚在脂肪中，所以该提案重点是脂肪中的节奏破坏组织是代谢性疾病发展的促成因素。我们假设AHR直接激活破坏脂肪组织中的分子昼夜节律时钟，并在大脑时钟之间产生不良脂肪组织；代谢综合征在时钟中断之后发展。最后，我们假设该保护节奏性将减轻AHR激活对代谢参数的有害影响。该提案结合在一起检查系统性代谢参数和行为昼夜节律和分子研究的方法专注于AHR介导的抑制代谢基因的机制，这些基因受昼夜节律调节。具体的 AIM I探索AHR激活状态对SCN和脂肪组织节奏的影响，并建立基本 AHR激活对这两个振荡器系统的影响的差异。目的我探索行为昼夜节律使用芳基烃受体缺陷型小鼠（AHRKO），节奏和对AHR激活状态差异的反应，具有AHR（CA-AHR）的本构激活的小鼠和用AHR激动剂治疗的野生型小鼠。 AIM II探索 AHR介导的脂解基因上的节奏破坏的分子机制，这是已知的靶标昼夜节律转录因子，时钟和BMAL1，重点是AHR和E-Box-之间的相互作用介导的转录。该项目为培训本科生和研究生提供了一个框架为生物医学科学的职业做准备。该提案突出了一种新型的异生物动作机制在代谢综合征的发展中，并洞悉了年度疗法的潜力治疗糖尿病和代谢综合征。