Mechanisms by Which Bone Marrow Adipose Tissue Expands During Calorie Restriction

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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.