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

脂肪组织对新陈代谢和整体健康具有重要意义。现在已经确定，脂肪不是一个被动的能量储存组织，正如它曾经被认为的那样，脂肪是一个动态的组织，它对不断变化的生理需求和系统信号做出反应，并分泌各种具有代谢意义的有效激素。脂肪组织内的主要细胞类型是脂肪细胞，最近的研究表明，脂肪细胞的类型存在异质性，包括不同的功能特性。使用细胞能量学对脂肪细胞进行分类可以定义两大类：储存能量的脂肪细胞（“白色”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，不止一种类型的脂肪细胞可以驻留在一个单一的脂肪库中；特别是，在啮齿类动物的皮下脂肪储存库中，主要是白色的，也有具有棕色脂肪细胞特性的脂肪细胞，称为褐色脂肪细胞（‘ brite ‘）或’ beige ’脂肪细胞。此外，这些脂肪细胞的数量是动态的，响应系统信号和环境的变化。随着肥胖个体数量的不断增加，脂肪细胞分散能量的潜在影响已经引起了人们对详细阐明这一生物学的热情，期望这些知识将为开发新的治疗方法提供基础，除了提高我们对细胞和分子生物学的总体理解之外。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缺口。在我们对生理系统信号如何在这些机械途径上汇聚的理解上，还有一个额外的知识缺口。通过条件缺失小鼠模型，我们发现Klf15是米色脂肪细胞生成的有效调节因子。我们将使用最先进的分子和细胞生物学方法来揭示Klf15调节这一过程的机制