Role of GPER in Obesity and Lipid Metabolism.
GPER 在肥胖和脂质代谢中的作用。
基本信息
- 批准号:10680278
- 负责人:
- 金额:$ 4.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AdipocytesAdultAgonistAnti-Inflammatory AgentsAtherosclerosisBiological AssayBiological ModelsBody WeightCRISPR/Cas technologyCardiovascular DiseasesCaringCell LineCell SurvivalCellsChronicComplexDesire for foodDiabetes MellitusDiseaseDisease ProgressionEstradiolEstrogen Nuclear ReceptorEstrogen Receptor alphaEstrogen Receptor betaEstrogen ReceptorsEstrogensExhibitsFatty acid glycerol estersFemaleGPER geneGene ExpressionGenerationsGenesGenus HippocampusGoalsHomeostasisHormonesHydrogen PeroxideHyperlipidemiaHypertensionInflammationInflammatoryInterleukin-1 betaInterleukin-6InterventionKnock-outKnockout MiceKnowledgeLaboratoriesLigandsLipaseLipidsLipolysisLiver diseasesMediatingMedicalMembraneMetabolicMetabolic DiseasesMetabolic dysfunctionMetabolismMitochondriaMusNational Health and Nutrition Examination SurveyObese MiceObesityOutcomeOverweightOxidative StressPathway interactionsPhysiologicalPhysiological ProcessesPlayPublic HealthReceptor ActivationReceptor SignalingRegulationRespirationRiskRoleSignal TransductionSmokingStress TestsSupplementationSystems DevelopmentTNF geneTestingTherapeuticTimeTissuesUnited StatesWeight GainWestern BlottingWild Type Mouseadipokinesagedantagonistantioxidant enzymebody systemcomorbiditycostcytokinedrug developmentimprovedin vivoinflammatory markerinhibitorlipid biosynthesislipid metabolismmalenon-genomicnovel therapeuticsobesity treatmentpreventable deathprotein expressionreceptor expressionreproductive developmenttherapeutic developmenttreatment strategy
项目摘要
PROJECT SUMMARY/ABSTRACT
Obesity poses as a serious and worsening public health issue in the United States and is the second
most common cause of preventable death behind smoking. Obesity is associated with the risk of developing
additional comorbidities, such as hypertension, atherosclerosis, and diabetes.
Estrogens (primarily 17β-estradiol, referred to as E2) can ameliorate weight gain and multiple aspects
of metabolic dysfunction. The effects of estrogens are mediated through multiple estrogen receptors (ERs),
including the classical nuclear ERs (ERα and ERβ), which traditionally regulate gene expression, and the 7-
transmembrane G protein-coupled estrogen receptor (GPER), which predominantly mediates rapid “non-
genomic” signaling. Our preliminary results suggest a potential intervention employing a highly selective GPER
agonist, with promising outcomes against multiple negative effects of obesity. With the opportunity to employ
the GPER-selective agonist G-1 as a novel therapeutic for obesity, understanding the direct effects of GPER in
adipocytes is critical. The long-term goal is to determine whether selective activators of GPER, such as G-1,
can improve lipid homeostasis, oxidative stress, and inflammation in adipocytes. The overall objective of this
proposal is to understand the mechanisms of E2-mediated effects via GPER in metabolic regulation,
specifically in adipocytes. The central hypothesis to be tested is whether GPER signaling directly improves lipid
homeostasis, oxidative stress, inflammation, and mitochondrial function in adipocytes. These findings will
inform drug development by making significant advancements in our knowledge regarding the role of GPER in
obesity and lipid metabolism, ultimately advancing the current insufficient therapeutic treatment options
available for obesity. The specific aims of this proposal are: Aim 1: Evaluate the roles of GPER in lipid
metabolism of adipocytes. The working hypothesis for this aim is that GPER’s effects on obesity are in part
mediated by direct actions on lipid metabolism on adipocytes. Aim 2: Determine the role of GPER in
oxidative stress, inflammation, and mitochondrial function in adipocytes. The working hypothesis for this
aim is that GPER plays a direct protective role against oxidative stress, inflammation, and improves
mitochondrial function in adipocytes.
This proposal will investigate the direct effects of GPER in adipocytes pertaining to lipid homeostasis,
oxidative stress, inflammation, and mitochondrial function, with the potential to significantly advance the study
of novel therapeutics protecting against obesity.
项目摘要/摘要
在美国,肥胖是一个严重且日益恶化的公共卫生问题,是第二大
吸烟是导致可预防死亡的最常见原因。肥胖与罹患癌症的风险有关
其他合并症,如高血压、动脉粥样硬化和糖尿病。
雌激素(主要是17β-雌二醇,简称E2)可以改善体重增加和多个方面
代谢功能障碍。雌激素的作用是通过多个雌激素受体(ER)介导的,
包括传统上调节基因表达的经典核内ER(ERα和ERβ),以及7-
跨膜G蛋白偶联雌激素受体(GPER),它主要介导快速的“非...
基因组“信号。我们的初步结果表明,使用高度选择性的GPER进行潜在的干预
激动剂,对肥胖的多种负面影响有希望的结果。有机会雇用
GPER选择性激动剂G-1作为治疗肥胖症的新药物,了解GPER在
脂肪细胞是至关重要的。长期目标是确定GPER的选择性激活剂,如G-1,
可以改善脂肪细胞中的脂质平衡、氧化应激和炎症。这样做的总体目标是
建议了解雌激素通过GPER在代谢调节中的作用机制。
尤其是在脂肪细胞中。有待检验的中心假设是GPER信号是否直接改善血脂
脂肪细胞的动态平衡、氧化应激、炎症和线粒体功能。这些发现将
通过在我们关于GPER在药物开发中的作用的知识方面取得重大进展来为药物开发提供信息
肥胖和脂代谢,最终推进目前治疗方案的不足
适用于肥胖。这项建议的具体目标是:目标1:评估GPER在血脂中的作用
脂肪细胞的代谢。这个目标的工作假设是,GPER对肥胖的影响在一定程度上是
通过直接作用于脂肪细胞上的脂类代谢而介导。目标2:确定GPER在
脂肪细胞的氧化应激、炎症和线粒体功能。关于这一点的工作假设
目的是GPER对氧化应激、炎症起到直接的保护作用,并改善
脂肪细胞中的线粒体功能。
这项建议将研究GPER在脂肪细胞中与脂质动态平衡有关的直接影响,
氧化应激、炎症和线粒体功能,有可能显著推进这项研究
预防肥胖的新疗法。
项目成果
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