Mechanisms by Which Bone Marrow Adipose Tissue Expands During Calorie Restriction

项目摘要 脂肪组织遍布全身，脂肪细胞可以有非常独特的 功能取决于它们所在的利基环境。一种未被研究的脂肪组织类型 是骨髓脂肪组织(BMAT)，它位于骨骼内部，是骨骼的一部分 骨髓。BMAT可占骨髓体积的70%，约占总脂肪的10% 然而，人们对这些细胞的功能知之甚少。BMAT是高度动态的， 在各种情况下扩张，包括肥胖、糖尿病、骨质疏松症、衰老、雌激素 缺乏、厌食和卡路里限制(CR)。BMAT扩展和扩展的机制 BMAT扩张在全身生理学中的作用还知之甚少。 我们对CR之后的BMAT扩展特别感兴趣，因为这是 其中大多数其他类型的脂肪组织质量减少。我们的目标是了解为什么 BMAT在CR后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，并确定是什么信号驱动BMAT扩张。一 BMAT在CR期间扩张的潜在机制是通过过量的糖皮质激素。 与循环中糖皮质激素过多有关的几种情况，如库欣病， 已被证明也会导致BMAT量的增加。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 大量实验来验证总体假设，即在CR之后，BMAT在 生理适应和过量糖皮质激素通过改变BMAT而驱动BMAT扩张 基因表达。 BMAT生物学领域一直受到提纯和操纵骨能力的限制 骨髓脂肪细胞(BMA)，同时避免所有其他类型的细胞在骨髓利基。至 为了验证我们的假设，我们开发了一系列新的小鼠模型来选择性地测量 在BMA中表达和删除感兴趣的基因。我们将使用这些模型来测量 BMA与其他脂肪库脂肪细胞CR后基因表达的比较 单核RNA测序。此外，我们将针对以下主要机制 糖皮质激素作用，糖皮质激素受体，在BMA内缺失。我们还有 开发了测量完全消融BMA如何影响全身生理的模型。 我们的结果将提供更好的了解BMAT的生理作用，无论是在基线和 在CR之后，并将潜在地发现针对BMAT的新的治疗方法 各种代谢性疾病。

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.