Adipose tissue macrophages are key contributors in metabolic disorders and inflammation linked to obesity. Macrophages play an important role in adipocyte mitochondrial function, lipid metabolism, and energy production. The processes causing macrophage infiltration and activation in adipose tissue following obesity, however, are largely unresolved. Previous studies have shown that the gap junctional protein connexin 43 (Cx43) is important for macrophage activation and phagocytosis. I explored the macrophage-specific involvement of Cx43 in the pathological remodelling of adipose tissue triggered by a high fat diet (HFD). Cx43 expression was increased in macrophages co-cultured with dying adipocytes in vitro, and also in macrophages affiliated with dying adipocytes in HFD-fed mice adipose tissue. Based on global gene expression analysis, Cx43-MKO animals were resilient to HFD-induced inflammatory responses in adipose tissue, potentially via P2X7-mediated signalling pathways. HFD-induced macrophage migration in adipose tissue was attenuated in Cx43-MKO mice. Furthermore, Cx43-MKO mice had decreased inflammasome activation in adipose tissues and improved glucose tolerance. These findings show that Cx43 expression in macrophages promotes inflammasome activation, which promotes HFD-induced metabolic dysfunction.