权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Hepatic Aryl Hydrocarbon Receptor Regulation of Obesity: Mechanisms of Action

肝芳基烃受体对肥胖的调节：作用机制

基本信息

批准号：
10701901
负责人：
Cornelis Johan Elferink
金额：
$ 35.62万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-09 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10701901
关键词：
ARNT gene ARNTL gene Affect Architecture Aromatic Polycyclic Hydrocarbons Aryl Hydrocarbon Receptor Binding Sites Biological Brain Brown Fat Cell Line Cell Separation Cells Chemicals Chromatin Circadian Rhythms Cues Deposition Development Dioxins Disparate Electron Transport Environmental Pollutants Estrogens Event Exhibits Exposure to FGF21 gene Female Gene Expression General Population Genes Genomics Glucagon Glucocorticoids Gonadal Steroid Hormones Health Hepatic Hepatocyte High Fat Diet Homeostasis Human Insulin Intervention Knockout Mice Ligands Liver Mediating Metabolic Metabolic Diseases Metabolic hormone Mitochondria Molecular Mus Muscle Mutate Obesity Outcome Pathway interactions Periodicity Phase Phenotype Physiological Physiological Processes Process Property Protein Family Proteins Receptor Signaling Regulation Reporting Research Respiration Response Elements Risk Signal Transduction Somatotropin Stat5 protein Suggestion Tertiary Protein Structure Testing Tetrachlorodibenzodioxin Therapeutic Thermogenesis Thyroid Hormones Transcriptional Regulation Transfection Variant Xenobiotics carbohydrate metabolism circadian clinical development combat conditional knockout diet-induced obesity estrogenic fibroblast growth factor 21 hepatoma cell improved in vivo lipid metabolism member novel strategies pollutant preservation prime editing promoter receptor expression reconstitution response sexual dimorphism single-cell RNA sequencing single-minded protein success transcription factor transcriptome transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT The Aryl Hydrocarbon Receptor (AhR) is a member of the eukaryotic Per-ARNT-Sim (PAS) domain protein family that regulates adaptive and toxic responses to a variety of chemical pollutants, including polycyclic aromatic hydrocarbons and polychlorinated dioxins, most notably 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We recently showed that female, but not male liver-specific AhR conditional knockout mice are protected from high fat diet-induced obesity and exhibited improved metabolic homeostasis. The sexually dimorphic phenotype was attributed to increased hepatic expression of fibroblast growth factor 21 (FGF21) in females. FGF21 is a circulating hepatokine that affects carbohydrate and lipid metabolism, and induces thermogenesis in white and brown fat deposits by uncoupling mitochondrial respiration from the electron transport chain. These properties have motivated research into the development of FGF21-based therapeutics to combat metabolic disorders and obesity, but with little success to date. Hence, understanding how AhR activity controls Fgf21 expression may point to novel strategies or targets for the development of clinical interventions. Hepatic Fgf21 expression is also under the control of sex steroids and is subject to circadian rhythms. The latter observation is of note because both the AhR and its partner protein, the AhR Nuclear Translocator (ARNT), belong to the same PAS protein family as several of the circadian rhythm (clock) proteins, including brain and muscle ARNT-like 1 (BMAL1). Hepatic AhR expression exhibits a 24 h periodicity in phase with BMAL1 oscillations, suggestive of co-regulation of these proteins. Moreover, ARNT shares considerable sequence similarity to BMAL1, and an AhR-BMAL1 interaction has been reported, implying that interactions between circadian rhythmicity and AhR signaling are reciprocal and significant. The central premise of this application is, that hepatic Fgf21 expression represents a nexus where AhR signaling and the molecular events underlying sexual dimorphism and circadian rhythmicity, coalesce. We hypothesize that a comprehensive assessment of how these physiologically disparate signaling processes are integrated is required to fully understand AhR regulated Fgf21 expression, and its impact on diet-induced obesity. To test the hypothesis, we propose experimental strategies that preserve the physiological context and genomic milieu. Specific Aim 1 will examine Fgf21 promoter functionality from the standpoint of AhR, ARNT, and BMAL1 activity as a function of circadian rhythmicity. Specific Aim 2 will use single-cell transcriptomics to identify diurnal changes in liver gene expression due to AhR, ARNT, and BMAL1 activity. Specific Aim 3 will interrogate sexually dimorphic Fgf21 expression as a function of estrogenicity. The Specific Aims constitute distinct yet integrated endeavors to mechanistically understand how the AhR regulates Fgf21 expression in the liver, under experimental conditions that preserve the physiological processes responsible for the sexual dimorphism and circadian rhythmicity in the context of a native genomic milieu that retains normal chromatin architecture.

项目概要/摘要芳基烃受体 (AhR) 是真核 Per-ARNT-Sim (PAS) 结构域蛋白的成员调节对多种化学污染物（包括多环污染物）的适应性和毒性反应的家族芳香烃和多氯二恶英，尤其是 2,3,7,8-四氯二苯并-对二恶英 (TCDD)。我们最近表明，肝脏特异性 AhR 条件性敲除小鼠可以免受雌性而非雄性的影响高脂肪饮食引起的肥胖并表现出改善的代谢稳态。性二态性该表型归因于女性成纤维细胞生长因子 21 (FGF21) 的肝脏表达增加。 FGF21 是一种循环肝因子，影响碳水化合物和脂质代谢并诱导产热通过将线粒体呼吸与电子传递链解偶联，在白色和棕色脂肪沉积物中产生作用。这些特性促使人们研究开发基于 FGF21 的疗法来对抗代谢紊乱和肥胖，但迄今为止收效甚微。因此，了解 AhR 活动如何控制 Fgf21 表达可能为临床干预的开发指明新的策略或目标。肝脏 Fgf21 表达也受到性类固醇的控制，并受到昼夜节律的影响。这后一个观察结果值得注意，因为 AhR 及其伙伴蛋白 AhR 核转运蛋白 (ARNT)，与几种昼夜节律（时钟）蛋白属于同一 PAS 蛋白家族，包括大脑和肌肉 ARNT 样 1 (BMAL1)。肝脏 AhR 表达表现出 24 小时周期性，与 BMAL1 振荡，表明这些蛋白质的共同调节。此外，ARNT 还拥有相当大的份额与 BMAL1 的序列相似性，并且已经报道了 AhR-BMAL1 相互作用，这意味着相互作用昼夜节律和 AhR 信号传导之间是互惠且显着的。这句话的中心前提是应用是，肝脏 Fgf21 表达代表了 AhR 信号传导和分子事件之间的联系潜在的性别二态性和昼夜节律相结合。我们假设一个全面的需要评估这些生理上不同的信号传导过程如何整合，以充分了解 AhR 调节 Fgf21 表达及其对饮食引起的肥胖的影响。为了检验假设，我们提出了保留生理背景和基因组环境的实验策略。具体目标 1 将从 AhR、ARNT 和 BMAL1 活性作为函数的角度检查 Fgf21 启动子功能昼夜节律。具体目标 2 将使用单细胞转录组学来识别肝脏的昼夜变化 AhR、ARNT 和 BMAL1 活性导致的基因表达。具体目标 3 将审问性别二态性 Fgf21 表达作为雌激素的函数。具体目标构成了独特但综合的努力在实验中从机制上了解 AhR 如何调节肝脏中的 Fgf21 表达保持负责性别二态性和昼夜节律的生理过程的条件在保留正常染色质结构的天然基因组环境中的节律性。