Osteocytic Connexin 43 Hemichannel Regulation of Adiposity - 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.
