Molecular responses and physiological implications to systemic stimuli in adipocyte progenitor cells

脂肪祖细胞对全身刺激的分子反应和生理学意义

• 批准号: 10420760
• 负责人: Brian J Feldman
• 金额: $ 51.36万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10420760
• 关键词: Adipocytes; Adipose tissue; Biology; Categories; Cellular biology; Data; Development; Diet; Elements; Environment; Equilibrium; Exposure to; Family member; Foundations; Generations; Genes; Goals; Health; Heterogeneity; Hormones; Individual; Knowledge; Lipids; Mammals; Metabolic; Metabolic Diseases; Metabolism; Molecular; Molecular Biology; Obesity; Pathway interactions; Physiological; Population; Process; Property; Rodent; Role; Signal Transduction; Stimulus; Therapeutic; Tissues; Translating; cell type; expectation; hormonal signals; mouse model; novel therapeutic intervention; progenitor; programs; public health relevance; response; stem cells; subcutaneous

Adipose tissue has important implications for metabolism and general health. It is now well established that, rather than being a passive tissue for energy storage, as it was once perceived, adipose is a dynamic tissue that responds to changing physiological needs and systemic signals as well as secretes a variety of potent hormones with metabolic implications. The primary cell type within adipose tissue is the adipocyte and more recent advances have elucidated that there is heterogeneity in types of adipocytes, including divergent functional properties. Using cellular energetics to classify types of adipocytes defines two broad categories: adipocytes that store energy (‘white’ adipocytes) and adipocytes that disperse energy (‘brown’ adipocytes). Perhaps most intriguingly, more than one type of adipocyte can reside within a single adipose depot; in particular, within subcutaneous adipose depots in rodents, which are primarily white, there are also adipocytes that have properties of brown adipocytes, referred to as brown-in-white (‘brite’) or ‘beige’ adipocytes. Furthermore, the number of these adipocytes is dynamic, responding to changes in the systemic signals and environments. As the number of individuals with obesity continues to rise, the potential implications of adipocytes that disperse energy has generated enthusiasm for elucidating this biology in detail with the expectation that this knowledge will provide a foundation for the development of novel therapeutic approaches, in addition to advancing our understanding of cell and molecular biology in general. Yet, there is a knowledge gap in our understanding of the molecular mechanisms that direct this important process. There is an additional knowledge gap in our understanding of how physiological systemic signals converge on these mechanistic pathways. Using a conditional deletion mouse model, we identified Klf15 as a potent regulator of the generation of beige adipocytes. We will use state-of-the-art molecular and cell biology approaches to expose the mechanisms by which Klf15 regulates this process

脂肪组织对代谢和一般健康具有重要意义。现在已经很好地确定，脂肪曾经被认为是一种动态组织，而不是作为能量存储的被动组织，它响应了变化的物理需求和系统信号，并分泌了具有代谢含义的各种潜在马匹。脂肪组织中的主要细胞类型是脂肪细胞，最近的进步已经阐明了脂肪细胞类型（包括功能性能不同）的异质性。使用细胞能来对脂肪细胞的类型进行分类，定义了两个广泛的类别：存储能量（“白色”脂肪细胞）和脂肪细胞的脂肪细胞和分散能量的脂肪细胞（“棕色”脂肪细胞）。也许最有趣的是，多种类型的脂肪细胞可以驻留在一个脂肪仓库中。特别是，在啮齿动物的皮下脂肪沉积物中，首先是白色的，也有脂肪细胞具有棕色脂肪细胞的特性，称为棕色 - 灰色（'brite'）或'米色'脂肪细胞。此外，这些脂肪细胞的数量是动态的，对系统信号和环境的变化做出了反应。随着肥胖症患者的数量不断增加，分散能量的脂肪细胞的潜在影响也引起了人们对这种生物学详细阐明这种生物学的热情，即期望这种知识将为新型热方法的发展提供基础，此外，除了促进我们对细胞和分子生物学的理解。然而，我们对指导这一重要过程的分子机制的理解存在知识差距。我们对物理系统信号如何在这些机械途径上汇聚的理解存在额外的知识差距。使用条件缺失鼠标模型，我们将KLF15确定为有效的，我们将使用最先进的分子和细胞生物学方法来揭示KLF15调节此过程的机制