Mechanisms of adipocyte loss in mouse models of familial partial lipodystrophy 2
家族性部分脂肪营养不良小鼠模型脂肪细胞丢失的机制2
基本信息
- 批准号:10748790
- 负责人:
- 金额:$ 4.08万
- 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:2023-07-01 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAdipocytesAdipose tissueAdultAgeAllelesArchitectureBlood GlucoseCell DeathCellsCharacteristicsChromatinDNA BindingDataDepositionDevelopmentDiabetes MellitusDown-RegulationFamilial partial lipodystrophyFatty LiverFluorescent in Situ HybridizationFoundationsFunctional disorderFutureGene ExpressionGenesGlobal ChangeHealthHepaticHomeostasisHumanHyperlipidemiaImmuneInflammatoryInjectionsInsulinKnock-outKnockout MiceKnowledgeLamin Type ALeadLeptinLipidsLipodystrophyLipolysisLocationLoxP-flanked alleleMaintenanceMetabolic dysfunctionMitochondriaModelingMolecularMorphologyMusMutationNuclearNuclear LaminaPathogenicityPathway interactionsPatientsPhenotypePositioning AttributeProteinsProteomicsPubertyPublishingRare DiseasesReporterRoleSecondary toShapesStructureTamoxifenTestingTracerTriglyceridesUp-RegulationVariantVisceraladipocyte biologyadiponectinautosomecomparison controlexperimental studyfunctional lossgene synthesisin vivoinsightlipid biosynthesislipid metabolismmouse modelnew therapeutic targetpostnatalpreventsubcutaneoustherapeutic targettranscription factortranscriptome sequencingvector
项目摘要
PROJECT SUMMARY/ABSTRACT
Lipodystrophies are rare diseases, characterized by a striking loss, redistribution, and dysfunction of adipose
tissue, and accompanied by metabolic dysfunction. Familial partial lipodystrophy 2 (FPLD2) is the most
common type of lipodystrophy, caused by mutations in LMNA, which encodes the nuclear lamina proteins
lamin A/C. Lamin A/C is crucial for nuclear function and controls gene expression, but its role in adipocyte
maintenance and function is incompletely understood. Our lab created a constitutive adipocyte specific Lmna
knockout mouse model (LmnaADKO) to better characterize the roles of Lmna in adipocytes. LmnaADKO mice
develop adipose tissues that are subsequently lost starting at 4 weeks of age; LmnaADKO mice have hepatic
steatosis and reduced circulating leptin concentrations, closely recapitulating FPLD2. Analyses of LmnaADKO
mice suggest that lamin A/C is required for adipocyte maintenance, substantially advancing our mechanistic
understanding, since previous studies did not reveal how loss of Lmna function leads to lipodystrophy.
To study mechanisms of how knockout of Lmna in adipocytes leads to subsequent loss of adipocytes, we
generated mice in which Lmna can be inducibly knocked out with administration of tamoxifen (LmnaiADKO). This
approach allows us to use adult mice, which have more adipose tissue, and to temporally synchronize
adipocyte loss. In preliminary experiments, we have tested multiple mechanisms in vivo that could contribute to
loss of adipocytes in LmnaiADKO mice. Altered adipogenesis seems unlikely, considering that functional white
adipose tissue (WAT) develops in LmnaADKO mice and patients with FPLD2. We also did not observe signs of
increased lipolytic capacity or increased acute cell death in WAT lacking Lmna in adipocytes. However, we did
observe that adipocytes lacking Lmna are visibly smaller and misshapen compared to controls, suggesting
adipocytes are losing their lipid stores, and are unable to maintain viability. Bulk RNA-seq and proteomics from
LmnaiADKO WAT revealed downregulation of lipogenic pathways, and upregulation of inflammatory genes. We
hypothesize that lamin A/C is required to maintain mature adipocyte characteristics, and that absence of
functional lamin A/C leads to adipocyte loss through reduced lipogenic gene expression, driven by altered
interactions between Lmna and chromatin. My project will test this hypothesis by (1) evaluating changes in
lipogenic and mitochondrial genes in Lmna knockout adipocytes and performing DamID and FISH to study
changes in chromatin-lamina interactions that may underlie changes in gene expression and (2) assessing
decreased de novo lipogenesis in LmnaiADKO mice, in addition to restoring lipogenic gene expression to Lmna
KO adipocytes to prevent WAT loss. Ultimately, these studies will reveal underlying molecular mechanisms of
FPLD2, uncovering novel therapeutic targets for lipodystrophy patients while bolstering our understanding of
fundamental adipocyte biology.
项目概要/摘要
脂肪营养不良是一种罕见疾病,其特征是脂肪显着减少、重新分布和功能障碍
组织,并伴有代谢功能障碍。家族性部分性脂肪营养不良 2 (FPLD2) 是最常见的
常见类型的脂肪营养不良,由编码核纤层蛋白的 LMNA 突变引起
层压板空调。核纤层蛋白 A/C 对核功能至关重要并控制基因表达,但其在脂肪细胞中的作用
维护和功能不完全了解。我们的实验室创建了组成型脂肪细胞特异性 Lmna
敲除小鼠模型(LmnaADKO),以更好地表征 Lmna 在脂肪细胞中的作用。 LmnaADKO小鼠
脂肪组织开始发育,随后从 4 周龄开始消失; LmnaADKO 小鼠有肝
脂肪变性和循环瘦素浓度降低,与 FPLD2 密切相关。 LmnaADKO 分析
小鼠表明核纤层蛋白 A/C 是脂肪细胞维持所必需的,这大大推进了我们的机制
理解,因为之前的研究没有揭示 Lmna 功能的丧失如何导致脂肪营养不良。
为了研究脂肪细胞中 Lmna 的敲除如何导致随后脂肪细胞损失的机制,我们
产生的小鼠中,通过施用他莫昔芬 (LmnaiADKO) 可以诱导敲除 Lmna。这
该方法允许我们使用具有更多脂肪组织的成年小鼠,并在时间上同步
脂肪细胞损失。在初步实验中,我们在体内测试了多种可能有助于
LmnaiADKO 小鼠脂肪细胞损失。考虑到功能性白色,改变脂肪生成似乎不太可能
LmnaADKO 小鼠和 FPLD2 患者体内出现脂肪组织 (WAT)。我们也没有观察到迹象
脂肪细胞中缺乏 Lmna 的 WAT 中的脂肪分解能力增加或急性细胞死亡增加。然而,我们做到了
观察到与对照组相比,缺乏 Lmna 的脂肪细胞明显更小且畸形,这表明
脂肪细胞正在失去其脂质储备,并且无法维持活力。批量 RNA 测序和蛋白质组学
LmnaiADKO WAT 揭示了脂肪生成途径的下调和炎症基因的上调。我们
假设需要核纤层蛋白 A/C 来维持成熟的脂肪细胞特征,并且缺乏
功能性核纤层蛋白 A/C 通过改变脂肪生成基因表达而导致脂肪细胞损失
Lmna 和染色质之间的相互作用。我的项目将通过(1)评估以下方面的变化来检验这一假设:
Lmna 敲除脂肪细胞中的脂肪生成和线粒体基因并进行 DamID 和 FISH 进行研究
染色质-核纤层相互作用的变化可能是基因表达变化的基础;(2) 评估
除了恢复 Lmna 的脂肪生成基因表达外,还减少了 LmnaiADKO 小鼠的从头脂肪生成
KO 脂肪细胞以防止 WAT 损失。最终,这些研究将揭示潜在的分子机制
FPLD2,揭示脂肪营养不良患者的新治疗靶点,同时增强我们对
基础脂肪细胞生物学。
项目成果
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