Current studies aim to understand the deleterious effects of adiposity on visceral organs such as the heart and liver. Less is understood about the effect of adipose tissue on the development and regulation of bone. Obesity is highly correlated with conditions of bone loss, including osteoporosis. Additionally, the loss of bone is associated with an increase in adiposity within the bone marrow niche. These bone marrow adipocytes (BMA) originate from the same progenitor cell as osteoblasts, the precursors to mature bone-forming cells. Activation of PPARg, an important transcription factor found primarily in adipocytes, drives adipogenesis at the expense of osteoblastogenesis. PPARg activation is also associated with reduced inflammation and the repartitioning of lipids away from organs ill-equipped to cope with a lipotoxic environment, making it a good target for insulin- sensitizing drugs known as Thiazolidines (TZD). Unfortunately, clinical use of TZDs is associated with increased risk for bone fractures due to impaired skeletal integrity. As such, maintaining skeletal health in obese patients, particularly those receiving TZD treatment, has become a critical challenge. Previously identified post-translational modifications (PTM) of PPARg have dissociated the insulin-sensitizing effects of TZD treatment from the negative outcomes. The constitutive deacetylation of Lys268 and Lys293 by conversion to Arginine residues in a mouse model has been shown to ameliorate bone loss and reduce marrow adiposity. To further elucidate the mechanism through which this PPARg PTM protects bone deterioration, the investigator proposes to uncover the functional role that bone marrow adipocytes play within the hematopoietic niche, including the extent to which BMA-derived adipokines contribute to skeletal remodeling. Specifically, she plans to identify adipsin as a key adipokine that is altered in response to PPARg deacetylation and is a potential modulator of the balance between marrow adipocytes and bone cells.
In Aim 1 the investigator will identify adipsin as a mediator of the bone protective effect caused by PPARg deacetylation. Furthermore, she plans to elucidate the mechanism through which adipsin mediates the crosstalk between bone and bone marrow adipocytes in Aim 2 by assessing the role of adipsin released from peripheral and bone marrow adipose tissue using primary cells and an adipsin knockout mouse model. In addition to its potential role in bone regulation, adipsin is known to be involved in the alternative pathway of the complement system.
In Aim 3 she plans to establish the role of the complement system in bone homeostasis through adipsin. Ultimately, this study will identify the molecular mechanism by which PPARg deacetylation selectively protects bone homeostasis. The identification of adipsin as a novel regulator of skeletal remodeling processes will advance the field of adipocyte biology by elucidating a novel adipokine to connect fat and bone.
Understanding the role of bone marrow adiposity in regulating bone homeostasis is crucial for the treatment of conditions of bone loss. By elucidating the mechanism through which PPARg deacetylation mitigates bone deterioration by adipokine signaling, this project will identify adipsin as a novel therapeutic target for the treatment of bone disorders, especially those caused by obesity and T2DM therapies.