Perilipin 5 in the Regulation of Adipose Tissue Function
Perilipin 5 在脂肪组织功能调节中的作用
基本信息
- 批准号:9920140
- 负责人:
- 金额:$ 40.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-07-01 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdipocytesAdipose tissueAdrenergic AgonistsAdultAttentionBiogenesisBrown FatCaloriesCapsid ProteinsCatecholaminesCell Differentiation processCell NucleusCell RespirationCellsCrista ampullarisCyclic AMP-Dependent Protein KinasesDataDiabetes MellitusDiseaseDoxycyclineEconomic BurdenElectron MicroscopyElementsEnergy MetabolismGene ExpressionGenetic ModelsGenetic TranscriptionGoalsHealthHeterogeneityHomeostasisHormonalHumanHuman bodyKnock-outKnowledgeLipaseLipidsMaintenanceMediatingMetabolicMitochondriaModelingMolecularMolecular ProfilingMorphologyMusNon-Insulin-Dependent Diabetes MellitusNuclearNutrientObesityObesity EpidemicOvernutritionOxidative PhosphorylationPathway interactionsPharmacologyPhosphorylationPhysiologicalPositioning AttributePre-Clinical ModelPrevalenceProteomicsPublicationsRegulationReportingResearchRespirationRoleSIRT1 geneSignal TransductionStimulusStressTherapeuticThermogenesisThinnessTissuesToxic effectWild Type Mouseadipocyte differentiationadult obesitycardiovascular risk factorgain of functionglucose metabolismhealthspanhormonal signalshuman maleimprovedindexingknockout genelipid metabolismloss of functionmouse modelnovelnovel therapeutic interventionnovel therapeuticsoverexpressionperilipinprogenitorprogramsresponsesubcutaneoustranscriptome sequencing
项目摘要
The rising prevalence of obesity and type 2 diabetes threatens to limit human health span and to impose overwhelming economic burdens. New therapeutic approaches are urgently needed. Since the discovery within the last decade of functional brown and beige adipocytes in adult humans, much attention has focused on exploiting the ability of these thermogenic adipocytes to dissipate excess energy as heat through uncoupled respiration. Brown adipocytes are concentrated in discrete depots of brown adipose tissue; whereas, beige adipocytes develop from progenitors within white adipose tissue (WAT) in response to specific stimuli, including cold and β3-adrenergic receptor agonists. Recent research has revealed key elements of the transcriptional machinery that governs brown/beige cell differentiation, as well as numerous factors that activate brown/beige adipocytes. Importantly, relatively little is known about the intracellular factors that integrate hormonal and environmental signals with the nuclear transcriptional machinery that activates thermogenesis in adipocytes. This project investigates one such factor, Perilipin 5, which was originally discovered as a lipid droplet coat protein expressed in highly oxidative tissues, including brown adipose tissue. Perilipin 5 has been studied primarily as a regulator of lipase access and activity on the lipid droplet. Another function of Perilipin 5 has emerged from the discovery that, following its phosphorylation by protein kinase A, Perilipin 5 boosts gene expression related to oxidative metabolism and to the thermogenic program through physical interaction with SIRT1 and PGC-1α in the nucleus. The underlying hypothesis of this application is that increasing Perilipin 5 in thermogenic adipocytes will sensitize them to activation by stimuli such as cold exposure and β3-adrenergic receptor agonists and enable effective energy dissipation to address obesity and improve metabolic health. The overall goal of this project is to establish a preclinical model for increasing the capacity of brown/beige adipocytes to dissipate excess energy acquired through overnutrition. Specific Aim 1 will define the physiological role of Perilipin 5 in brown adipose tissue (BAT) thermogenesis and systemic glucose and lipid metabolism in adult mice by means of novel mouse models of inducible, BAT-specific overexpression and knockout of Perilipin 5. Specific Aim 2 will investigate the role of Perilipin 5 in maintaining mitochondrial integrity in BAT during cold stress and will explore the heterogeneity of BAT adipocytes defined by Perilipin expression. Specific Aim 3 will determine whether Perilipin 5 is sufficient to sensitize WAT to beiging in adult mice subjected to physiological (cold exposure) or pharmacological (β3-adrenergic receptor agonist) stimuli, and whether Perilipin 5 is necessary for WAT beiging triggered by these stimuli. Completion of these Aims will establish Perilipin 5 as a critical integrator of hormonal and transcriptional signaling in thermogenic adipocytes and may suggest novel therapeutic strategies to unleash the thermogenic potential of fat cells.
肥胖症和2型糖尿病患病率的上升可能会限制人类的健康寿命,并造成压倒性的经济负担。迫切需要新的治疗方法。自从在过去的十年中在成人中发现了功能性的棕色和米色脂肪细胞以来,人们的注意力主要集中在利用这些产热脂肪细胞通过解偶联呼吸将多余的能量释放为热量的能力上。棕色脂肪细胞集中在离散的棕色脂肪组织中;而米色脂肪细胞是由白色脂肪组织(WAT)内的前体细胞在特定刺激(包括冷和β3-肾上腺素能受体激动剂)的刺激下发育而来的。最近的研究揭示了控制棕色/米色细胞分化的转录机制的关键元素,以及激活棕色/米色脂肪细胞的众多因素。重要的是,人们对将激素和环境信号与激活脂肪细胞产热的核转录机制相结合的细胞内因子知之甚少。这个项目研究了一种这样的因子,Perilipin 5,它最初是作为一种脂滴外壳蛋白在高度氧化的组织中表达的,包括棕色脂肪组织。Perilipin 5主要作为脂滴上脂肪酶通路和活性的调节剂而被研究。Perilipin 5的另一个功能是,在被蛋白激酶A磷酸化后,Perilipin 5通过与细胞核中的sirt1和pgc-1α发生物理作用,促进与氧化代谢和产热程序相关的基因表达。这一应用的基本假设是,在生热脂肪细胞中增加Perilipin 5将使它们对冷暴露和β3-肾上腺素能受体激动剂等刺激的激活敏感,并能够有效地消耗能量以解决肥胖问题和改善代谢健康。这个项目的总体目标是建立一个临床前模型,以增加棕色/米色脂肪细胞的能力,以分散通过过度营养获得的多余能量。具体目的1将通过诱导、BAT特异性过表达和敲除Perilipin 5的新小鼠模型来确定Perilipin 5在成年小鼠棕色脂肪组织(BAT)产热和全身糖脂代谢中的生理作用。特殊目的2将研究Perilipin 5在冷应激期间维持BAT线粒体完整性中的作用,并将探索由Perilipin表达决定的BAT脂肪细胞的异质性。具体目标3将确定Perilipin 5是否足以在生理(冷暴露)或药物(β3-肾上腺素能受体激动剂)刺激下使成年小鼠的WAT对褐变敏感,以及Perilipin 5是否是由这些刺激触发的WAT褐变所必需的。这些目标的完成将使Perilipin 5成为生热脂肪细胞中激素和转录信号的关键整合因子,并可能提出释放脂肪细胞生热潜力的新的治疗策略。
项目成果
期刊论文数量(0)
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{{ truncateString('PERRY E BICKEL', 18)}}的其他基金
FASEB SRC on Lipid Droplets on the Move from Health to Disease
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9543174 - 财政年份:2018
- 资助金额:
$ 40.5万 - 项目类别:
Perilipin 5 in the Regulation of Adipose Tissue Function
Perilipin 5 在脂肪组织功能调节中的作用
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10735422 - 财政年份:2018
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$ 40.5万 - 项目类别:
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FLOTILLINS AND INSULIN-STIMULATED GLUCOSE TRANSPORT
FLOTILLINS 和胰岛素刺激的葡萄糖转运
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6697133 - 财政年份:2002
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FLOTILLINS 和胰岛素刺激的葡萄糖转运
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6436962 - 财政年份:2002
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7006950 - 财政年份:2002
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