Effects of Wnt/β-catenin signaling on adipocytes

Wnt/β-连环蛋白信号对脂肪细胞的影响

• 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
• 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

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.

摘要 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。 疾病经典的Wnt/β-catenin信号转导是间充质细胞增殖的重要调节因子， 命运决定和分化，抑制脂肪生成和促进成骨细胞生成。新兴 人类的遗传学证据已经将各种Wnt途径成员与体脂分布、肥胖和肥胖症联系起来。 代谢功能障碍，表明该途径在终末分化的脂肪细胞中起作用。的确， 最近对小鼠的研究发现了令人信服的证据，表明Wnt通路在小鼠体内起着重要作用， 在脂肪细胞代谢中的作用，特别是在致肥胖条件下。然而， Wnt途径及其在此背景下潜在分子机制仍不清楚。在我们最初的 实验，以表征这一途径的重要性，在终末分化的脂肪细胞，我们删除 Wntless，一种专门用于Wnt蛋白分泌的细胞内伴侣，或β-连环蛋白， 分子经典Wnt途径从培养的脂肪细胞和脂肪组织。两种方法都显示 脂肪细胞来源的Wnt或脂肪细胞中典型的Wnt/β-catenin信号传导的丢失协调地降低了 调节脂肪生成基因表达，导致新生脂肪生成和脂肪酸合成受损 单不饱和此外，这些对脂质代谢的影响是由Srebf 1和Mlxipl的抑制介导的， 已知脂肪生成酶表达的主要转录调节因子。在体内，缺失Wntless或β- 连环蛋白不影响维持普通饮食的小鼠的总体代谢。然而，我们的研究表明， 脂肪组织能够防御脂肪细胞特异性Wntless或β- 在周围基质血管细胞中通过Wnt信号的补偿性上调来调节连环蛋白。最后，长- 长期的营养过剩超过了这种补偿机制，使得Wls-/-和β-cat-/-小鼠都具有抵抗性， 饮食诱导的肥胖症和保护代谢功能障碍。在此，我们提出实验， 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 Wnt/β-catenin调控脂肪细胞基因表达和细胞功能的机制，以及细胞间Wnt/β-catenin 信号传导监测并补偿脂肪细胞中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学起关键作用的理解。 和脂肪组织的病理生理学。