Mechanisms of Glucocorticoid Action on Adipose Tissue Metabolism

糖皮质激素对脂肪组织代谢的作用机制

• 批准号: RGPIN-2021-03439
• 负责人: Beaudry, Jacqueline
• 金额: $ 2.04万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=742542
• 关键词: Mechanisms; Glucocorticoid; Action; Adipose; Tissue

Glucocorticoids (GCs), or stress hormones, play a role in regulating energy flux and structural changes in fat tissue. Studies have identified a strong link between high levels of GCs and inappropriate accumulation of fat in mammalians. Although white (stores excess energy) and brown (expends excess energy as heat) fat tissues function in very different ways, they have evolved to become very dynamic organs that specialize in regulating whole-body energy balance. We know that chronic and high levels of GCs increase the distribution and amount of fat tissue, but we still do not understand how GCs cause these abnormalities. Previously, I demonstrated that activated GCs were increased within centralized depots in rats treated with GCs and fed a high-fat diet. I also showed that specific GC inhibitors do not change GC-induced central fat accumulation, despite lower levels of activated GCs, indicating that mechanisms behind GC activators may be dispensable for fat storage or metabolism. However, to date, this question has not been resolved. Consequently, the long-term objective of my research is to better understand how fat is influenced by hormonal control, which in-turn affects how fat tissue expands and grows. I will study fat biogenesis through the response of white and brown fat to conditions of high levels of GCs and how it relates to energy balance. I am particularly interested in this area of research due to emerging evidence demonstrating the importance of fat for integral communication between bodily systems. In the next 5 years I will pursue 3 short-term goals: 1. To investigate how GCs increase fat loading into fat tissue 2. To explore specific pathways used in GC signaling in fat tissue in mice models 3. To identify hormones that are influenced by GC action in fat tissue I will address these goals by performing experiments in cell culture, primary fat models, as well as mouse models. Ultimately, this work will provide novel understanding of underlying mechanisms of GC action that will augment comprehension of fat biology, such as expansion and hormone regulation that govern energy balance. This research will train both BSc and MSc students. Scientific studies in my laboratory will provide trainees with hands-on research experience and science knowledge in the fields of nutrition, physiology, and metabolism that will be translatable to a variety of scientific careers. My research plan will offer a challenging and stimulating environment for all personnel and allow them to gain highly sought after skills, such as conceptualizing complex problems, performing hypothesis driven research, developing effective time management, refining proper data analysis, and communicating effectively through presentations and publications. Accordingly, this research program will provide new and impactful insights into fundamental aspects of the biogenesis of fat, and will offer excellent scientific training to the personnel involved in this research.

糖皮质激素（GC）或应激激素在调节脂肪组织的能量通量和结构变化中起作用。研究已经确定了高水平的GC和不适当的脂肪积累之间的密切联系。虽然白色（储存多余的能量）和棕色（消耗多余的能量作为热量）脂肪组织以非常不同的方式发挥作用，但它们已经进化成为非常活跃的器官，专门调节全身能量平衡。我们知道，长期和高水平的GC增加了脂肪组织的分布和数量，但我们仍然不明白GC是如何导致这些异常的。以前，我证明了在用GC治疗并喂食高脂饮食的大鼠中，激活的GC在集中仓库内增加。我还表明，特定的GC抑制剂不改变GC诱导的中央脂肪积累，尽管较低水平的活化GC，表明GC激活剂背后的机制可能是脂肪储存或代谢。然而，迄今为止，这一问题尚未得到解决。因此，我研究的长期目标是更好地了解脂肪如何受到激素控制的影响，这反过来又影响脂肪组织如何扩张和生长。我将通过白色和棕色脂肪对高水平GC条件的反应以及它如何与能量平衡相关来研究脂肪的生物发生。我对这一领域的研究特别感兴趣，因为有新的证据表明脂肪对身体系统之间的整体沟通的重要性。 在接下来的五年里，我将追求三个短期目标：1。研究GC如何增加脂肪组织中的脂肪负荷2.探讨小鼠脂肪组织中GC信号传导的特异性通路。为了确定在脂肪组织中受GC作用影响的激素，我将通过在细胞培养、原发性脂肪模型以及小鼠模型中进行实验来解决这些目标。最终，这项工作将为GC作用的潜在机制提供新的理解，这将增强对脂肪生物学的理解，例如控制能量平衡的扩张和激素调节。 这项研究将培养学士和硕士学生。我实验室的科学研究将为学员提供营养，生理学和代谢领域的实践研究经验和科学知识，这些知识将转化为各种科学职业。我的研究计划将为所有人员提供一个具有挑战性和刺激性的环境，并使他们获得备受追捧的技能，如概念化复杂问题，进行假设驱动的研究，开发有效的时间管理，完善适当的数据分析，并通过演示文稿和出版物进行有效沟通。因此，这项研究计划将为脂肪生物发生的基本方面提供新的和有影响力的见解，并将为参与这项研究的人员提供出色的科学培训。