Mechanisms by Which Bone Marrow Adipose Tissue Expands During Calorie Restriction

热量限制期间骨髓脂肪组织扩张的机制

• 批准号: 9907442
• 负责人: Rebecca L. Schill
• 金额: $ 6.12万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-04 至 2021-09-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907442
• 关键词: Address; Adipocytes; Adipose tissue; Adrenal Cortex; Aging; Animals; Anorexia; Biology; Bone Marrow; Bone Marrow Ablation; Caloric Restriction; Cell Nucleus; Cell physiology; Cells; Cushing Syndrome; Diabetes Mellitus; Disease; Estrogens; Gene Expression; Genes; Genetic; Glucocorticoid Receptor; Glucocorticoids; Goals; Hormones; Human; Hydrocortisone; Injections; Location; Marrow; Measures; Mediator of activation protein; Metabolic Diseases; Metabolism; Modeling; Mus; Nutrient; Obesity; Osteogenesis; Osteoporosis; Patients; Physiological; Physiological Adaptation; Physiology; Pituitary-dependent Cushing' s disease; Play; Population; Process; Reporting; Role; Series; Signal Transduction; Stress; System; Testing; Tissue Expansion; Tissues; absorption; adiponectin; bone; bone loss; bone mass; bone metabolism; cell type; design; experimental study; genetic approach; innovation; interest; mouse model; new therapeutic target; novel; novel therapeutic intervention; programs; response; tool; transcriptome sequencing

Project Summary Adipose tissue is located throughout the body, and adipocytes can have very unique functions depending on the niche in which they reside. One understudied type of adipose tissue is bone marrow adipose tissue (BMAT), which is located inside the bone as part of the bone marrow. BMAT can make up to 70% of the bone marrow volume and is ~10% of total adipose mass; however, very little is known about the function of these cells. BMAT is highly dynamic and expands under a variety of conditions, including obesity, diabetes, osteoporosis, aging, estrogen deficiency, anorexia, and calorie restriction (CR). The mechanism by which BMAT expands and the role of BMAT expansion in whole-body physiology is poorly understood. We are particularly interested in BMAT expansion following CR because it is a situation in which most other types of adipose tissue decrease in mass. Our goals are to understand why BMAT responds differently than other types of adipose tissue following CR, determine the physiological importance of this expansion, and identify what signals drive BMAT expansion. One potential mechanism by which BMAT expands during CR, is through excess glucocorticoids. Several conditions involving excess circulating glucocorticoids, such as Cushing’s Disease, have been shown to also cause increased BMAT volume. Similarly, in healthy patients, BMAT volume increases following injection of synthetic glucocorticoids. Therefore, we have designed a series of experiments to test the overall hypothesis that following CR, BMAT plays an important role in physiological adaptation and that excess glucocorticoids drive BMAT expansion by altering BMAT gene expression. The field of BMAT biology has been limited by the ability to purify and manipulate bone marrow adipocytes (BMA), while avoiding all other cell types within the bone marrow niche. To test our hypothesis, we have developed a series of novel mouse models to selectively measure gene expression and delete genes of interest within BMA. We will use these models to measure gene expression in BMA compared to adipocytes from other adipose depots following CR using single-nuclei RNA-sequencing. Additionally, we will target the primary mechanism of glucocorticoid action, the glucocorticoid receptor, for deletion within BMA. We have also developed models to measure how complete ablation of BMA impacts whole-body physiology. Our results will provide a better understanding of BMAT’s physiological role, both at baseline and following CR, and will potentially identify new therapeutic approaches to target BMAT for a variety of metabolic diseases.

项目概要 脂肪组织遍布全身，脂肪细胞具有非常独特的功能。 功能取决于它们所在的利基市场。一种正在研究的脂肪组织类型 是骨髓脂肪组织（BMAT），位于骨骼内部，作为骨骼的一部分 骨髓。 BMAT 占骨髓体积的 70%，约占总脂肪的 10% 大量的;然而，人们对这些细胞的功能知之甚少。 BMAT 是高度动态且 在多种条件下都会扩张，包括肥胖、糖尿病、骨质疏松症、衰老、雌激素 缺乏、厌食​​和热量限制（CR）。 BMAT 扩展的机制 BMAT 扩张在全身生理学中的作用尚不清楚。 我们对 CR 之后的 BMAT 扩展特别感兴趣，因为这是以下情况： 大多数其他类型的脂肪组织质量减少。我们的目标是了解原因 CR 后 BMAT 的反应与其他类型的脂肪组织不同，确定 这种扩张的生理重要性，并确定哪些信号驱动 BMAT 扩张。一 CR 期间 BMAT 扩展的潜在机制是通过过量的糖皮质激素。 一些涉及过量循环糖皮质激素的疾病，例如库欣病，已 已被证明也会导致 BMAT 体积增加。同样，在健康患者中，BMAT 体积 注射合成糖皮质激素后增加。因此我们设计了一系列 的实验来检验总体假设，即 CR 之后，BMAT 在 生理适应以及过量的糖皮质激素通过改变 BMAT 来驱动 BMAT 扩张 基因表达。 BMAT 生物学领域受到纯化和操纵骨骼能力的限制 骨髓脂肪细胞（BMA），同时避免骨髓生态位内的所有其他细胞类型。到 为了检验我们的假设，我们开发了一系列新颖的小鼠模型来选择性地测量 基因表达并删除 BMA 内感兴趣的基因。我们将使用这些模型来衡量 使用 CR 后与来自其他脂肪库的脂肪细胞相比，BMA 中的基因表达 单核RNA测序。此外，我们将针对主要机制 糖皮质激素作用，糖皮质激素受体，用于 BMA 内的删除。我们还有 开发了模型来测量 BMA 的完全消融如何影响全身生理机能。 我们的结果将有助于更好地了解 BMAT 在基线和基础上的生理作用 CR 后，并有可能确定针对 BMAT 的新治疗方法 多种代谢性疾病。