Deciphering age-dependent beige adipocyte failure
解读年龄依赖性米色脂肪细胞衰竭
基本信息
- 批准号:10589822
- 负责人:
- 金额:$ 42.37万
- 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:2022-03-15 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAdipocytesAdipose tissueAdrenergic AgentsAgeAgingAgreementAutomobile DrivingBiochemicalBiogenesisBlood GlucoseBlood VesselsBody fatCardiovascular DiseasesCell AgingCell CommunicationCellsCessation of lifeClinicalCommunicationConsumptionDeteriorationDevelopmentFailureFatty acid glycerol estersFosteringFunctional disorderGenerationsGeneticGenetic ModelsGenetic TranscriptionGlucoseGoalsHealthHelper-Inducer T-LymphocyteHomeostasisHumanImmuneImmunologicsIncidenceIndividualInterleukinsLinkLongevityLymphoid CellMammalsMetabolicMetabolic DiseasesMetabolic dysfunctionMetabolismMethodsModelingMolecularMusNon-Insulin-Dependent Diabetes MellitusNonesterified Fatty AcidsObesityObesity EpidemicOutputPathway interactionsPhenotypePhysiologicalPlatelet-Derived Growth Factor beta ReceptorPopulationProcessRampRejuvenationResearchRoleSignal TransductionSignaling MoleculeSourceTestingTherapeuticTissuesType 2 diabeticUp-Regulationadipocyte differentiationage relatedagedclinical efficacycold temperaturecombatdesensitizationhealthspanimprovedjuvenile animalmetabolic fitnessmouse modelnovelnovel therapeuticsobese patientspharmacologicprematurepreservationpreventprogenitorrecruitresponsesenescencestem cell functionstem cellsthermal stresstranscriptomicsyoung adult
项目摘要
PROJECT SUMMARY:
Cold temperature (<15°C) exposure stimulates perivascular beige adipocyte progenitor cells (bAPCs) to
generate beige adipocytes. Beige adipocytes act as cellular furnaces to burn blood glucose and free fatty acids
to generate heat. Recent studies have shown the metabolic benefits of beige adipocytes, suggesting potential
clinical efficacy for obese patients and type 2 diabetics. However, the potential to form cold-induced beige
adipocytes declines with age, creating a pivotal challenge to the therapeutic promise for older individuals, many
of whom constitute the obesity epidemic. Our studies begin to unravel how aging suppresses beige adipogenic
potential and identifies new ways to rejuvenate beige fat cell biogenesis to restore metabolic fitness in aged
mammals. Our previous studies have linked cellular senescence, a state of cellular arrest, of bAPCs to the age-
associated decline in beige adipose tissue. In an attempt to find additional mechanisms blocking beige fat
biogenesis in aged mammals, we found that the expression and signaling of platelet derived growth factor
receptor beta (Pdgfrβ) is increased in aged bAPCs. Moreover, ablation of Pdgfrβ within the beige adipose lineage
restored beige adipocyte generation and improved metabolic health in aged (not young) mice. Despite beige fat
formation in aged Pdgfrβ-deficient mice, lineage-tracing studies revealed that auxiliary source(s) generated
beige adipocytes. In agreement, senescence tests demonstrated that Pdgfrβ neither promoted nor reversed
cellular senescence. Instead, we found that Pdgfrβ signaling prevents group 2 innate lymphoid cell (ILC2)
recruitment and activation within iWAT depots. Mechanistically, we identified that Pdgfrβ elicits signals via Stat1
to suppress the ILC2-inducer, interleukin-33 (IL-33), to control WAT ILC2 activity. Finally, we identify sympathetic
tone as a significant regulator of age-induced Pdgfrβ expression. Our aims will elucidate the physiological and
cellular role of Pdgfrβ in regulating beige fat biogenesis under aging and obese conditions. We will elucidate the
Pdgfrβ-Stat1 signaling mechanism in bAPCs to control ILC2 recruitment via IL-33. We uncover how sympathetic
output regulates Pdgfrβ expression to drive the age-dependent beige adipogenic failure. These findings will
implicate Pdgfrβ signaling as a central node in the bAPC aging process. Importantly, this application will identify
factors that reverse age-dependent beige adipogenic failure with a direct clinical utility to combat excess body
fat and metabolic dysfunction to extend lifespan and restore health.
项目总结:
低温(<;15℃)刺激血管周围米色脂肪细胞前体细胞(BAPC)
产生米色脂肪细胞。米色脂肪细胞充当燃烧血糖和游离脂肪酸的细胞熔炉
以产生热量。最近的研究表明,米色脂肪细胞对代谢有好处,这表明它具有潜在的潜力。
对肥胖患者和2型糖尿病患者的临床疗效。然而,形成寒冷诱导的米色的可能性
脂肪细胞随着年龄的增长而减少,这对许多老年人的治疗前景构成了关键挑战
其中构成了肥胖症的流行。我们的研究开始揭开衰老是如何抑制米色脂肪生成的
潜在并确定了恢复米色脂肪细胞生物生成以恢复老年人代谢健康的新方法
哺乳动物。我们之前的研究已经将bAPC的细胞衰老,一种细胞停滞状态,与年龄-
相关的米色脂肪组织减少。试图找到阻止米色脂肪的额外机制
在老年哺乳动物的生物发生中,我们发现血小板衍生生长因子的表达和信号转导
老年bAPC受体β(PDGFRβ)表达增加。此外,在米色脂肪谱系内消融PDGFRβ
恢复了老年(而不是年轻)小鼠的米色脂肪细胞生成并改善了代谢健康。尽管有米色脂肪
在老年PDGFRβ缺陷小鼠中的形成,谱系追踪研究发现辅助来源(S)产生
米色脂肪细胞。一致的是,衰老测试表明,pdgfrβ既没有促进也没有逆转。
细胞衰老。相反,我们发现PDGFRβ信号阻止了第二组固有淋巴样细胞(ILC2)
IWAT仓库内的招募和激活。从机制上讲,我们发现PDGFRβ通过信号转导通路1产生信号
抑制ILC2诱导物白介素33(IL-33),以控制Wat ILC2活性。最后,我们发现,我们同情
Tone是AGE诱导的PDGFRβ表达的重要调节因子。我们的目标将阐明生理学和
衰老和肥胖条件下PDGFRβ在调节米色脂肪生物生成中的细胞作用。我们将澄清
BAPC中的PDGFRβ-STAT1信号机制通过IL-33控制ILC2的招募。我们发现了我们有多么同情
OUTPUT调节PDGFRβ的表达,以驱动年龄依赖性的米色成脂失败。这些发现将
暗示PDGFRβ信号在bAPC老化过程中是一个中心节点。重要的是,此应用程序将标识
逆转年龄相关性米色成脂失败的因素对对抗身体过剩具有直接的临床效用
脂肪和代谢障碍,以延长寿命和恢复健康。
项目成果
期刊论文数量(0)
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Daniel Carl Berry其他文献
Daniel Carl Berry的其他文献
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{{ truncateString('Daniel Carl Berry', 18)}}的其他基金
Cell cycle regulators control adiposity and metabolism
细胞周期调节剂控制肥胖和新陈代谢
- 批准号:
8784402 - 财政年份:2014
- 资助金额:
$ 42.37万 - 项目类别:
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