Effects of Wnt/β-catenin signaling on adipocytes

Wnt/β-连环蛋白信号对脂肪细胞的影响

基本信息

批准号：
10337561
负责人：
Ormond A MacDougald
金额：
$ 44.46万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-15 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10337561
关键词：
ATAC-seq Adipocytes Adipose tissue Affect Back Binding Bioinformatics Blood Vessels Body fat CTNNB1 gene Cardiovascular Diseases Cell Nucleus Cell physiology Cells Chronic Disease Complex DNA Binding Data Diet Enzymes Evaluation Exhibits FABP4 gene Fatty Acids Felis catus Financial compensation Fluorescence-Activated Cell Sorting Functional disorder Gene Expression Genetic Genetic Transcription Genetic study Glycolysis High Fat Diet Homeostasis Human Human Genetics Hypertrophy Impairment Inflammatory Insulin Resistance Investigation Knockout Mice LDL-Receptor Related Protein 1 Ligands Light Link Mediating Membrane Mesenchymal Messenger RNA Metabolic Metabolic Pathway Metabolic dysfunction Metabolism Molecular Molecular Chaperones Monitor Mus Non-Insulin-Dependent Diabetes Mellitus Nutritional Obese Mice Obesity Overnutrition Oxidative Phosphorylation Pathway interactions Phenotype Physiological Physiology Play Population Production Protein Secretion Proteins Regulation Reporting Repression Resistance Risk Factors Role Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Stromal Cells System TCF Transcription Factor Testing Tissues Up-Regulation WNT Signaling Pathway Wnt proteins Work adipocyte differentiation base beta catenin blood glucose regulation cell type chromatin immunoprecipitation diet-induced obesity experimental study extracellular vesicles fatty acid metabolism flexibility improved in vivo infancy inhibitor lipid biosynthesis lipid metabolism member obesogenic promoter receptor response single-cell RNA sequencing

项目摘要

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.

抽象的肥胖是许多次要慢性病的关键危险因素，包括2型糖尿病和心血管疾病。典型的Wnt/β-catenin信号传导是良好细胞的重要调节剂命运的确定和分化，抑制脂肪形成并促进成骨细胞生成。新兴人类的遗传证据将各种Wnt途径成员与体内脂肪分布，肥胖和代谢功能障碍，表明该途径在末端分化的脂肪细胞中运行。的确，在小鼠中的最新研究发现了令人信服的证据，表明Wnt途径起着重要的作用在脂肪细胞代谢中的作用，特别是在肥胖状态下。但是，确切的功能角色在这种情况下，Wnt途径及其基本的分子机制尚不清楚。在我们的最初实验以表征该途径在末端差异脂肪细胞中的重要性，我们删除了 Wntless，一种用于Wnt蛋白分泌的专用细胞内伴侣，或β-catenin，中央信号传导分子规范的Wnt途径来自培养的脂肪细胞和脂肪组织。两种方法都揭示了脂肪细胞衍生的WNT或脂肪细胞中依次的Wnt/β-catenin信号的丧失调节脂肪生成基因表达，从而导致从头脂肪生成和脂肪酸受损单不饱和。此外，这些对脂质代谢的影响是通过SREBF1和MLXIPL的表达介导的已知的脂肪生物酶表达的已知主要转录调节剂。在体内，无wnt或β-的缺失 Catenin不会影响Chow Diet维持的小鼠的全球代谢。但是，我们的研究表明脂肪时代能够捍卫脂肪细胞特异性损失或β-的惊人现象通过补偿性上调Wnt信号传导在周围的基质 - 血管细胞中。最后，长期术语营养不良覆盖了这种补偿机制，使得wls - / - 和β-cat - / - 小鼠均具有抗性饮食引起的肥胖症并免受代谢功能障碍的保护。在此，我们建议实验进一步研究Wnt信号在脂肪组织中的作用。具体而言，我们将研究机制 Wnt/β-catenin通过其中调节脂肪细胞基因表达和细胞功能，以及细胞间Wnt 信号传导监视并补偿脂肪细胞中Wnt信号传导的损失。成功完成这些目标将提高我们对这种古老的信号通路如何对生理至关重要的理解和脂肪组织的病理生理学。