OBJECTIVE: Sympathetic nervous system and immune cell interactions play key roles in the regulation of metabolism. For example, recent convergent studies have shown that macrophages regulate obesity through brown adipose tissue (BAT) activation and beiging of white adipose tissue (WAT) via effects upon local catecholamine availability. However, these studies have raised issues about the underlying mechanisms involved including questions regarding the production of catecholamines by macrophages, the role of macrophage polarization state and the underlying intracellular signaling pathways in macrophages that might mediate these effects. METHODS: To address such issues we generated mice lacking Irs2, which mediates the effects of insulin and interleukin 4, specifically in LyzM expressing cells (Irs2LyzM-/- mice). RESULTS: These animals displayed obesity resistance and preservation of glucose homeostasis on high fat diet feeding due to increased energy expenditure via enhanced BAT activity and WAT beiging. Macrophages per se did not produce catecholamines but Irs2LyzM-/- mice displayed increased sympathetic nerve density and catecholamine availability in adipose tissue. Irs2-deficient macrophages displayed an anti-inflammatory transcriptional profile and alterations in genes involved in scavenging catecholamines and supporting increased sympathetic innervation. CONCLUSIONS: Our studies identify a critical macrophage signaling pathway involved in the regulation of adipose tissue sympathetic nerve function that, in turn, mediates key neuroimmune effects upon systemic metabolism. The insights gained may open therapeutic opportunities for the treatment of obesity.