Date of Award
8-8-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Bone marrow adipose tissue (BMAT) is a unique fat depot located within the skeletal system that takes up a large portion of the total bone marrow volume and contains tremendous amounts of energy that can be potentially utilized to fuel the body. However, largely attributed to its strong resistance to lipolytic stimuli and its persistent accumulation in various physiological and pathological conditions, the exact function of BMAT within the bone and how it is regulated throughout the body remains largely unclear. This dissertation sought to better understand the unique role of BMAT within the bone marrow niche by first reviewing the previous literature suggestive of its potential energy-supplying and endocrine functions, as well as its neural and systemic regulatory mechanisms (Chapter 1). This is followed by studying its ectopic expansion and adaptations with age and disease using a genetically modified “fat-free” mouse model (Chapter 2). Next, we identified a novel neural-systemic lipolytic pathway of BMAT that mediates its catabolism for end-stage utilization (Chapter 3). Finally, this dissertation concludes with a prospective investigation of its protective role for bone in settings of cancer-associated cachexia (Chapter 4). BMAT is a metabolically and clinically relevant fat depot that exists within bone. Two subtypes of BMAT, regulated and constitutive, reside in hematopoietic-rich red marrow and fatty yellow marrow, respectively, and exhibit distinct characteristics compared to peripheral fat such as white and brown adipose tissues. Bone marrow adipocytes (BMAds) are evolutionally preserved in most vertebrates, start development after birth and expand throughout life, and originate from unique progenitor populations that control bone formation and hematopoiesis. Mature BMAds also interact closely with other cellular components of the bone marrow niche, serving as a nearby energy reservoir to support the skeletal system, a signaling hub that contributes to both local and systemic homeostasis, and a final fuel reserve for survival during starvation. Though BMAT and bone are often inversely correlated, more BMAT does not always mean less bone, and the prevention of BMAT expansion as a strategy to prevent bone loss remains questionable. BMAT adipogenesis and lipid metabolism are regulated by the nervous systems and a variety of circulating hormones. Altogether, Chapter 1 provides a comprehensive overview of the local and systemic functions of BMAT and discusses the regulation of this unique adipose tissue depot in health and disease. Bone marrow adipocytes accumulate with age and in diverse disease states. However, their origins and adaptations in these conditions remain unclear, impairing our understanding of their context-specific endocrine functions and relationship with surrounding tissues. In Chapter 2, by analyzing bone and adipose tissues in the lipodystrophic ‘fat-free’ mouse, we define a novel, secondary adipogenesis pathway that relies on the recruitment of adiponectin-negative stromal progenitors. This pathway is unique to the bone marrow and is activated with age and in states of metabolic stress in the fat-free mouse model, resulting in the expansion of bone marrow adipocytes specialized for lipid storage with compromised lipid mobilization and cytokine expression within regions traditionally devoted to hematopoiesis. This finding further distinguishes bone marrow from peripheral adipocytes and contributes to our understanding of bone marrow adipocyte origins, adaptations, and relationships with surrounding tissues with age and disease. Several adipose depots, including constitutive bone marrow adipose tissue (cBMAT), resist conventional lipolytic cues, making them metabolically non-responsive. However, under starvation, wasting, or cachexia, the body can eventually catabolize these stable adipocytes through unknown mechanisms. To study this, in Chapter 3, we developed a mouse model of brain-evoked depletion of all fat, including cBMAT, independent of food intake. Genetic, surgical, and chemical approaches demonstrated that depletion of stable fat required adipose triglyceride lipase-dependent lipolysis but was independent of local nerves, the sympathetic nervous system, and catecholamines. Instead, concurrent hypoglycemia and hypoinsulinemia activated a potent catabolic state by suppressing lipid storage and increasing catecholamine-independent lipolysis via downregulation of cell-autonomous lipolytic inhibitors Acvr1c, G0s2, and Npr3. This was also sufficient to delipidate classical adipose depots. Overall, this work defines unique adaptations of stable adipocytes to resist lipolysis in healthy states while isolating a potent in vivo neurosystemic pathway by which the body can rapidly catabolize all adipose tissues. Cancer cachexia is a complication of late-stage malignancy characterized by marked loss of body weight, anorexia, asthenia, and anemia. Patients with cancer cachexia suffer from severe wasting of muscle and fat that can be accompanied by the gelatinous transformation of the bone marrow (GTBM), a condition defined by focal loss of BMAT and hematopoietic cells with the deposition of extracellular gelatinous substance in the marrow space. Many cachexic patients with GTBM also develop osteopenia with a high incidence of fractures. In Chapter 4, we begin to test whether BMAT can serve as an energy reserve during the early stages of cancer cachexia to support local bone health using a Colon-26 carcinoma-induced cancer cachexia mouse model. Cachexia developed at various time points ranging from 2- to 5-weeks after the injection with the growth of a tumor weighing between 0.7 to 2.5 grams. Peripheral white adipose tissue was largely absent at the endpoint. Mice that retained BMAT had minimal bone loss, whereas mice with prolonged tumor exposure and BMAT depletion displayed cortical bone loss and porosity. This suggests that, when present, BMAT may protect cortical bone from cancer cachexia-induced bone loss. Conversely, after BMAT is fully depleted, the bone may become more susceptible to cachexia-associated erosion. Future work will clarify these results using a BMAT conditional model of lipolysis resistance. Overall, these findings inform the potential of targeting BMAT as a therapeutic option for maintaining bone health in cachexia. Together, instead of just a space filler or even a negative regulator of bone, this dissertation has provided novel insights into BMAT as an active cellular component of the marrow niche that contributes to skeletal homeostasis under health and disease, and also as a backup energy reserve under extreme conditions of end-stage starvation, wasting, or cachexia.
Language
English (en)
Chair
Erica Scheller
Committee Members
Chao Zhou