2048-LB: Activation of Connexin Hemichannels and PGE2 Release in Osteocytes Reduce Global Adiposity and Improve Metabolic Homeostasis while Preserving Lean Mass

Background: Research into signaling molecules for obesity therapies has largely overlooked the role of bone, particularly osteocytes (Ocy), which play crucial roles in biomechanical, inflammatory, & metabolic signaling. Connexin 43 (Cx43) hemichannels (HCs), abundant in Ocy, facilitate cellular communication. Research has shown these HCs, sensitive to mechanical cues, exchange molecules, such as prostaglandin E2 (PGE₂), influencing bone quality and differentiation of adipose tissue (AT) & skeletal muscle (SkM).

Objective: Investigate the role of Ocy Cx43 HCs in mediating cross-organ regulation between AT & SkM in obesity.

Methods: In vivo we used transgenic mice with overexpression of Cx43 dominant negative mutants in Ocy: R76W (inhibited gap junctions (GJs), enhanced HCs) & Δ130-136 (inhibited HCs & GJs), or a monoclonal Cx43(M2) antibody that opens Cx43 HCs, ±high-fat diet, and in vitro, conditioned media (CM) collected from fluid flow-stimulated Ocy.

Results: Impaired HCs (Δ130-136) contributed to increased AT, while enhanced HC activity (R76W/M2) reduced it, resulting in improved energy expenditure and preservation of SkM/lean mass. This association was linked to Cx43 HC-mediated elevation in global PGE₂ levels. Specifically, Δ130-136 mice exhibited up to an 8% increase in %fat and decrease in lean mass. Conversely, augmentation of HCs (R76W/M2) increased activity, food intake, & calorie expenditure, while mitigating up to a 4-fold increase in %fat & reducing weight (p=0.01), glucose, triglycerides, AT hypertrophy/whitening, & liver AT. Treatment with Ocy CM inhibited adipogenic differentiation of AT-derived stem cells, which was undone by CM from Ocy treated with a HC-blocking antibody.

Conclusion: These studies provide new insight into the role of Ocy Cx43 HC in metabolic health, through the regulation of AT/lean mass, and present it as a unique target for combatting obesity, with PGE₂ being a major regulator.