Effects of Wnt/β-catenin signaling on adipocytes
Effects of Wnt/β-catenin signaling on adipocytes
批准号:
10337561
负责人:
Ormond A MacDougald
金额:
$44.46万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-12-15 至 2025-11-30
关键词:
ATAC-seqAdipocytesAdipose tissueAffectBackBindingBioinformaticsBlood VesselsBody fatCTNNB1 geneCardiovascular DiseasesCell NucleusCell physiologyCellsChronic DiseaseComplexDNA BindingDataDietEnzymesEvaluationExhibitsFABP4 geneFatty AcidsFelis catusFinancial compensationFluorescence-Activated Cell SortingFunctional disorderGene ExpressionGeneticGenetic TranscriptionGenetic studyGlycolysisHigh Fat DietHomeostasisHumanHuman GeneticsHypertrophyImpairmentInflammatoryInsulin ResistanceInvestigationKnockout MiceLDL-Receptor Related Protein 1LigandsLightLinkMediatingMembraneMesenchymalMessenger RNAMetabolicMetabolic PathwayMetabolic dysfunctionMetabolismMolecularMolecular ChaperonesMonitorMusNon-Insulin-Dependent Diabetes MellitusNutritionalObese MiceObesityOvernutritionOxidative PhosphorylationPathway interactionsPhenotypePhysiologicalPhysiologyPlayPopulationProductionProtein SecretionProteinsRegulationReportingRepressionResistanceRisk FactorsRoleSignal PathwaySignal TransductionSignaling MoleculeSignaling ProteinStromal CellsSystemTCF Transcription FactorTestingTissuesUp-RegulationWNT Signaling PathwayWnt proteinsWorkadipocyte differentiationbasebeta cateninblood glucose regulationcell typechromatin immunoprecipitationdiet-induced obesityexperimental studyextracellular vesiclesfatty acid metabolismflexibilityimprovedin vivoinfancyinhibitorlipid biosynthesislipid metabolismmemberobesogenicpromoterreceptorresponsesingle-cell RNA sequencing
中文摘要
摘要
肥胖是许多继发性慢性疾病的关键风险因素,包括2型糖尿病和心血管疾病。
疾病。经典的Wnt/β-catenin信号转导通路是间充质细胞的重要调节因子
命运决定和分化,抑制脂肪生成,促进成骨细胞生成。新兴
人类的遗传证据已将各种Wnt通路成员与身体脂肪分布、肥胖和
代谢功能障碍,表明这一途径在终末分化的脂肪细胞中是可行的。的确,
最近在小鼠身上进行的研究发现了令人信服的证据,表明Wnt途径发挥着重要作用
在脂肪细胞代谢中的作用,特别是在肥胖条件下。然而,其确切的功能角色
在这种情况下,Wnt途径及其潜在的分子机制仍不清楚。在我们的初始阶段
我们删除了在终末分化的脂肪细胞中表征这一途径重要性的实验
Wnless,Wnt蛋白分泌的专用细胞内伴侣,或β-连环蛋白,中枢信号转导
培养的脂肪细胞和脂肪组织中的分子经典Wnt途径。这两种方法都揭示了
脂肪细胞来源的Wnts或典型的Wnt/β-catenin信号的丢失协调下调-
调节生脂基因表达,导致新生脂肪生成和脂肪酸受损
单不饱和度。此外,这些对脂代谢的影响是通过抑制Srebf1和MLXIPL介导的,
已知的脂肪生成酶表达的主要转录调节因子。体内缺失Wnless或β-
连环蛋白不影响饮食维持的小鼠的整体新陈代谢。然而,我们的研究揭示了
一种显著的现象,即脂肪组织能够防御脂肪细胞特异性丢失Wnless或β-
通过代偿上调周围基质-血管细胞中的Wnt信号来实现连环蛋白。最后,Long-
长期营养过剩覆盖了这种补偿机制,因此wls-/-和β-cat-/-小鼠都具有抵抗力
减少饮食引起的肥胖,并防止代谢功能障碍。在此,我们建议进行实验,以
进一步研究Wnt信号在脂肪组织中的作用。具体地说,我们将调查这些机制
Wnt/β-catenin通过什么调控脂肪细胞基因表达和细胞功能,以及细胞间Wnt是如何
信号监测和补偿脂肪细胞中Wnt信号的丢失。成功完成
这些目标将提高我们对这个古老的信号通路如何对生理学至关重要的理解
和脂肪组织的病理生理学。
英文摘要
Abstract
Obesity is a key risk factor for many secondary chronic illnesses, including type 2 diabetes and cardiovascular
disease. Canonical Wnt/β-catenin signaling is well-established as an important regulator of mesenchymal cell
fate determination and differentiation, inhibiting adipogenesis and promoting osteoblastogenesis. Emerging
genetic evidence in humans has linked various Wnt pathway members to body fat distribution, obesity, and
metabolic dysfunction, suggesting that this pathway is operative in terminally-differentiated adipocytes. Indeed,
recent studies in mice have uncovered compelling evidence suggesting that the Wnt pathway plays important
roles in adipocyte metabolism, particularly under obesogenic conditions. However, the exact functional roles of
the Wnt pathway and its underlying molecular mechanisms in this context remain unclear. In our initial
experiments to characterize the importance of this pathway in terminally-differentiated adipocytes, we deleted
Wntless, a dedicated intracellular chaperone for Wnt protein secretion, or β-catenin, the central signaling
molecule canonical Wnt pathway from cultured adipocytes and in adipose tissue. Both approaches revealed
that loss of adipocyte-derived Wnts or canonical Wnt/β-catenin signaling in adipocytes coordinately down-
regulates lipogenic gene expression, resulting in impaired de novo lipogenesis and fatty acid
monounsaturation. Further, these effects on lipid metabolism are mediated by repression of Srebf1 and Mlxipl,
known master transcriptional regulators of lipogenic enzyme expression. In vivo, deletion of Wntless or β-
catenin does not influence global metabolism in mice maintained on chow diet. However, our studies revealed
a striking phenomenon by which adipose tissues are able to defend adipocyte-specific loss of Wntless or β-
catenin by compensatory up-regulation of Wnt signaling in surrounding stromal-vascular cells. Finally, long-
term overnutrition overrides this compensatory mechanism, such that both Wls-/- and β-cat-/- mice are resistant
to diet-induced obesity and protected from metabolic dysfunction. Herein we propose experiments to
investigate further the roles of Wnt signaling in adipose tissue. Specifically, we will investigate the mechanisms
by which Wnt/β-catenin regulates adipocyte gene expression and cell functions, and how intercellular Wnt
signaling monitors and compensates for the loss of Wnt signaling in adipocytes. Successful completion of
these aims will improve our understanding of how this ancient signaling pathway is critical for the physiology
and pathophysiology of adipose tissues.
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会议论文
Effects of Wnt/β-catenin signaling on adipocytes
-
批准号:10540392
-
项目类别:
-
资助金额:$44.46万
-
财政年份:2021
-
负责人:Ormond A MacDougald
-
依托单位:
Mechanisms by which adipocytes adapt to cool environmental temperatures
-
批准号:10408152
-
项目类别:
-
资助金额:$39.62万
-
财政年份:2020
-
负责人:Ormond A MacDougald
-
依托单位:
Mechanisms of adipocyte loss in laminopathy-induced lipodystrophy in mice and humans
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批准号:10447012
-
项目类别:
-
资助金额:$35.1万
-
财政年份:2020
-
负责人:Ormond A MacDougald
-
依托单位:
Mechanisms of adipocyte loss in laminopathy-induced lipodystrophy in mice and humans
-
批准号:10029064
-
项目类别:
-
资助金额:$31.2万
-
财政年份:2020
-
负责人:Ormond A MacDougald
-
依托单位:
Mechanisms by which adipocytes adapt to cool environmental temperatures
-
批准号:10627980
-
项目类别:
-
资助金额:$39.62万
-
财政年份:2020
-
负责人:Ormond A MacDougald
-
依托单位:
Mechanisms of adipocyte loss in laminopathy-induced lipodystrophy in mice and humans
-
批准号:10212385
-
项目类别:
-
资助金额:$35.1万
-
财政年份:2020
-
负责人:Ormond A MacDougald
-
依托单位:
Mechanisms by which adipocytes adapt to cool environmental temperatures
-
批准号:10212377
-
项目类别:
-
资助金额:$39.62万
-
财政年份:2020
-
负责人:Ormond A MacDougald
-
依托单位:
Mechanisms of adipocyte loss in laminopathy-induced lipodystrophy in mice and humans
-
批准号:10837652
-
项目类别:
-
资助金额:$23.4万
-
财政年份:2020
-
负责人:Ormond A MacDougald
-
依托单位:
Multidisciplinary Training Program in Basic Diabetes Research
-
批准号:9421217
-
项目类别:
-
资助金额:$0.74万
-
财政年份:2014
-
负责人:Ormond A MacDougald
-
依托单位:
Multidisciplinary Training Program in Basic Diabetes Research
-
批准号:9339668
-
项目类别:
-
资助金额:$23.87万
-
财政年份:2014
-
负责人:Ormond A MacDougald
-
依托单位:
Role of Sweet Taste Receptors in Adipocyte Differentiation and Metabolism
-
批准号:8473862
-
项目类别:
-
资助金额:$31.37万
-
财政年份:2012
-
负责人:Ormond A MacDougald
-
依托单位:
Role of Sweet Taste Receptors in Adipocyte Differentiation and Metabolism
-
批准号:8828180
-
项目类别:
-
资助金额:$32.48万
-
财政年份:2012
-
负责人:Ormond A MacDougald
-
依托单位:
Role of Sweet Taste Receptors in Adipocyte Differentiation and Metabolism
-
批准号:8329028
-
项目类别:
-
资助金额:$32.52万
-
财政年份:2012
-
负责人:Ormond A MacDougald
-
依托单位:
Regulation of adipocyte differentiation and metabolism
-
批准号:7997583
-
项目类别:
-
资助金额:$9.24万
-
财政年份:2010
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负责人:Ormond A MacDougald
-
依托单位:
Adipose Tissue Core
-
批准号:10190912
-
项目类别:
-
资助金额:$15.74万
-
财政年份:2010
-
负责人:Ormond A MacDougald
-
依托单位:
Adipose Tissue Core
-
批准号:10425296
-
项目类别:
-
资助金额:$15.74万
-
财政年份:2010
-
负责人:Ormond A MacDougald
-
依托单位:
Adipose Tissue Core
-
批准号:10656195
-
项目类别:
-
资助金额:$15.74万
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财政年份:2010
-
负责人:Ormond A MacDougald
-
依托单位:
Role of Wnt in White and Brown Adipose Development
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批准号:7012798
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项目类别:
-
资助金额:$34.82万
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财政年份:2003
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负责人:Ormond A MacDougald
-
依托单位:
Roles for Wnt signaling in adipose tissue
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批准号:8284216
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项目类别:
-
资助金额:$34.83万
-
财政年份:2003
-
负责人:Ormond A MacDougald
-
依托单位:
Roles for Wnt signaling in adipose tissue
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批准号:7828153
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项目类别:
-
资助金额:$37.43万
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财政年份:2003
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负责人:Ormond A MacDougald
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依托单位:
国内基金
海外基金
支链氨基酸代谢紊乱调控“Adipocytes - Macrophages Crosstalk”诱发2型糖尿病脂肪组织功能和结构障碍的作用及机制
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批准号:81970721
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项目类别:面上项目
-
资助金额:55.0万元
-
批准年份:2019
-
负责人:陶凌
-
依托单位: