Osteocytic Connexin 43 Hemichannel Regulation of Adiposity

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PROJECT SUMMARY Obesity is a global epidemic and a major contributor to some of the leading causes of death in the U.S., including diabetes, heart disease, stroke, and certain types of cancer. Obesity plays a pleiotropic role in various metabolic processes, including whole-body energy metabolism. Maintenance of whole-body homeostasis involves the coordination of metabolic processes in multiple tissues, including adipose tissue and bone. Given its prominent role in multiple bodily processes, recent evidence points to bone as a significant player in whole-body energy metabolism. Myeloid-derived cells, specifically macrophages, that have been identified as a source of extramedullary adipose tissue, arise from hematopoietic stem cells originating from the bone marrow. Osteocytes comprise >90% of bone cells, are mechanosensors, and orchestrators of the bone remodeling process. Osteocytic connexin 43 (Ocy Cx43) is a transmembrane protein expressed in bone that forms hemichannels (HCs) that facilitate the communication of cells among themselves and with their environment. The postulation that Ocy Cx43 may have a key role in the modulation of adipose tissue, and consequently metabolism and disease progression, has never been investigated. By using transgenic mice expressing dominant-negative Cx43 mutants in osteocytes or monoclonal antibodies that open/close Cx43 HCs, our laboratory has shown that Ocy Cx43 HCs are responsible for changes in adipose formation, in correlation with modulation in myeloid cell populations. Thus, altering Ocy Cx43 activity could be a new therapeutic target for the treatment of metabolic diseases, including obesity. This research effort aims to understand how Ocy Cx43 HCs can improve metabolic health by reducing fat through myeloid cell regulation and evaluate this as a unique target for combatting obesity. This information will identify new therapeutic targets for obesity and metabolic diseases. A better understanding of the underlying mechanism connecting these tissues/cells will give us the ability to manipulate these environments to improve systemic energy metabolism and glucose homeostasis, and to combat fat formation.