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.

项目摘要/摘要芳基碳氢化合物受体（AHR）是真核每粒子（PAS）域蛋白的成员调节对各种化学污染物的适应性和有毒反应的家庭，包括多环子芳族烃和多氯二恶英，最著名的是2,3,7,8-四氯迪本佐-P-二恶英（TCDD）。我们最近表明，女性，但没有雄性肝脏特异性AHR条件敲除小鼠免受保护高脂肪饮食引起的肥胖症，表现出改善的代谢稳态。性二态表型归因于女性成纤维细胞生长因子21（FGF21）的肝表达增加。 FGF21是一种影响碳水化合物和脂质代谢的循环肝动物，并诱导热生成通过从电子传输链中解开线粒体呼吸，在白色和棕色脂肪沉积中。这些特性促使研究基于FGF21的疗法的发展以对抗代谢障碍和肥胖症，但迄今为止几乎没有成功。因此，了解AHR的活动控制FGF21表达可能指出了新的策略或临床干预发展的目标。肝FGF21表达也受性类固醇的控制，并受到昼夜节律。这后一个观察值之所以值得注意，是因为AHR及其伴侣蛋白AHR核转运剂均可注意（arnt），属于与几种昼夜节律（时钟）蛋白的同一PAS蛋白家族大脑和肌肉类似1（BMAL1）。肝AHR表达表现出24小时的周期性 BMAL1振荡，暗示着这些蛋白质的共调节。此外，Arnt分享了很大的序列与BMAL1相似，并且已经报道了AHR-BMAL1相互作用，这意味着相互作用在昼夜节律之间和AHR信号之间是相互且显着的。中心前提应用是，肝FGF21表达式表示AHR信号和分子事件的联系基本的性二态性和昼夜节律，结合。我们假设这是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完全集成了解AHR调节的FGF21表达及其对饮食引起的肥胖症的影响。为了检验假设，我们提出了保留生理环境和基因组环境的实验策略。具体目标1 将从AHR，ARNT和BMAL1活性作为功能的角度检查FGF21启动子功能昼夜节律。特定的目标2将使用单细胞转录组学识别肝脏的昼夜变化由于AHR，ARNT和BMAL1活性引起的基因表达。特定目标3将询问性二态 FGF21表达是雌激素的函数。具体目标构成了独特但综合的努力在实验性下，机械学上了解AHR如何调节肝脏中的FGF21表达保留负责性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的背景下，有节奏性。