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.

抽象的肥胖是许多继发性慢性疾病的关键危险因素，包括 2 型糖尿病和心血管疾病典型的 Wnt/β-连环蛋白信号传导被认为是间充质细胞的重要调节因子。命运决定和分化，抑制脂肪生成并促进成骨细胞生成。人类的遗传证据已将各种 Wnt 通路成员与身体脂肪分布、肥胖和肥胖联系起来。代谢功能障碍，表明该途径确实在终末分化的脂肪细胞中起作用。最近对小鼠的研究发现了令人信服的证据，表明 Wnt 通路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，其确切的功能作用。在我们最初的研究中，Wnt 通路及其潜在的分子机制仍不清楚。为了表征该途径在终末分化脂肪细胞中的重要性的实验，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-连环蛋白，中央信号传导两种方法均揭示了培养脂肪细胞和脂肪组织中的分子经典 Wnt 通路。脂肪细胞来源的 Wnt 或经典 Wnt/β-连环蛋白信号传导的损失协调下调调节脂肪生成基因表达，导致从头脂肪生成和脂肪酸受损此外，这些对脂质代谢的影响是通过抑制 Srebf1 和 Mlxipl 介导的。已知体内脂肪生成酶表达的主要转录调节因子，Wntless 或 β- 的缺失。然而，我们的研究表明，连环蛋白不会影响维持食物饮食的小鼠的整体代谢。脂肪组织能够防御脂肪细胞特异性 Wntless 或 β- 损失的惊人现象最后，通过补偿性上调周围基质血管细胞中的 Wnt 信号来调节连环蛋白。术语营养过剩超越了这种补偿机制，使得 Wls-/- 和 β-cat-/- 小鼠都具有抵抗力在此我们提出了实验来预防饮食引起的肥胖并防止代谢功能障碍。进一步研究 Wnt 信号在脂肪组织中的作用具体来说，我们将研究其机制。 Wnt/β-catenin 通过哪些途径调节脂肪细胞基因表达和细胞功能，以及细胞间 Wnt 如何发挥作用信号监测并补偿脂肪细胞中 Wnt 信号传导的损失。这些目标将提高我们对这一古老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。