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:
- 金额:$ 35.62万
- 依托单位:
- 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:
- 关键词:ARNT geneARNTL geneAffectArchitectureAromatic Polycyclic HydrocarbonsAryl Hydrocarbon ReceptorBinding SitesBiologicalBrainBrown FatCell LineCell SeparationCellsChemicalsChromatinCircadian RhythmsCuesDepositionDevelopmentDioxinsDisparateElectron TransportEnvironmental PollutantsEstrogensEventExhibitsExposure toFGF21 geneFemaleGene ExpressionGeneral PopulationGenesGenomicsGlucagonGlucocorticoidsGonadal Steroid HormonesHealthHepaticHepatocyteHigh Fat DietHomeostasisHumanInsulinInterventionKnockout MiceLigandsLiverMediatingMetabolicMetabolic DiseasesMetabolic hormoneMitochondriaMolecularMusMuscleMutateObesityOutcomePathway interactionsPeriodicityPhasePhenotypePhysiologicalPhysiological ProcessesProcessPropertyProtein FamilyProteinsReceptor SignalingRegulationReportingResearchRespirationResponse ElementsRiskSignal TransductionSomatotropinStat5 proteinSuggestionTertiary Protein StructureTestingTetrachlorodibenzodioxinTherapeuticThermogenesisThyroid HormonesTranscriptional RegulationTransfectionVariantXenobioticscarbohydrate metabolismcircadianclinical developmentcombatconditional knockoutdiet-induced obesityestrogenicfibroblast growth factor 21hepatoma cellimprovedin vivolipid metabolismmembernovel strategiespollutantpreservationprime editingpromoterreceptor expressionreconstitutionresponsesexual dimorphismsingle-cell RNA sequencingsingle-minded proteinsuccesstranscription factortranscriptometranscriptome sequencingtranscriptomics
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Cornelis Johan Elferink其他文献
Cornelis Johan Elferink的其他文献
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{{ truncateString('Cornelis Johan Elferink', 18)}}的其他基金
Gulf Coast Center for Precision Environmental Health
墨西哥湾沿岸精准环境健康中心
- 批准号:
10647883 - 财政年份:2019
- 资助金额:
$ 35.62万 - 项目类别:
Gulf Coast Center for Precision Environmental Health
墨西哥湾沿岸精准环境健康中心
- 批准号:
10390320 - 财政年份:2019
- 资助金额:
$ 35.62万 - 项目类别:
Administrative Supplement for Gulf Coast Center for Precision Environmental Health
墨西哥湾沿岸精准环境健康中心行政补充
- 批准号:
10436634 - 财政年份:2019
- 资助金额:
$ 35.62万 - 项目类别:
Aryl Hydrocarbon Receptor-Mediated Epigenetic Processes
芳基烃受体介导的表观遗传过程
- 批准号:
9124375 - 财政年份:2016
- 资助金额:
$ 35.62万 - 项目类别:
A Novel Paradigm for Aryl Hydrocarbon Receptor Signaling
芳基烃受体信号传导的新范例
- 批准号:
8896257 - 财政年份:2015
- 资助金额:
$ 35.62万 - 项目类别:
Gulf Coast Health Alliance: health Risks related to the Macondo Spill (GC-HARMS)
墨西哥湾沿岸健康联盟:与马孔多泄漏事件相关的健康风险 (GC-HARMS)
- 批准号:
8469037 - 财政年份:2011
- 资助金额:
$ 35.62万 - 项目类别:
Gulf Coast Health Alliance: health Risks related to the Macondo Spill (GC-HARMS)
墨西哥湾沿岸健康联盟:与马孔多泄漏事件相关的健康风险 (GC-HARMS)
- 批准号:
8727814 - 财政年份:2011
- 资助金额:
$ 35.62万 - 项目类别:
Gulf Coast Health Alliance: health Risks related to the Macondo Spill (GC-HARMS)
墨西哥湾沿岸健康联盟:与马孔多泄漏事件相关的健康风险 (GC-HARMS)
- 批准号:
8213830 - 财政年份:2011
- 资助金额:
$ 35.62万 - 项目类别:














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