The development of obesity, an imbalance between energy intake and energy expenditure, is associated with disordered cross-talk between the metabolic and immune systems. Insulin resistance, a hallmark of the obese state, is in part a consequence of increased adipose tissue inflammation and is characterized by increased classical macrophage (CAM) infiltration. Yet the genes and molecular mechanism(s) underlying these processes remain poorly understood. Insulin receptor substrate 2 (Irs2) is a critical signaling node through which both insulin and cytokines act to regulate cellular function and may therefore influence macrophage function. To understand the importance of Irs2 in both macrophage biology and energy homeostasis, we have generated mice lacking Irs2 in macrophages (Irs2lysozymeM-/-). When challenged with high fat diet, Irs2lysozymeM-/- mice were resistant to weight gain and fat accumulation in part due to increased energy expenditure. Moreover, they displayed improved glucose homeostasis. At the molecular level, there was decreased adipose tissue expression of inflammatory markers (CAM) that might explain the improved insulin sensitivity. Additionally, there was increased brown adipose tissue expression of thermogenic markers which may underpin the increased energy expenditure. mRNA sequencing analysis of bone marrow-derived macrophages (BMDM) treated with lipopolysaccharides (LPS) revealed that inflammatory signaling pathways, including the nucleotide-binding-oligomerization domain (NOD)-like receptor and the toll-like receptor signaling pathways were down-regulated in the Irs2lysozymeM-/- BMDM compared to control BMDM. This analysis also revealed that targets of Krüppel-like factor 4 (KLF4), a transcription factor implicated in macrophage polarization, were up-regulated in LPS-treated Irs2lysozymeM-/- BMDM. Unbiased metabolomics approach also revealed that the levels of secreted citrulline, a by-product of nitric oxide synthesis and a CAM marker, are reduced in LPS- treated Irs2lysozymeM-/- BMDM. These studies implicate a novel role for macrophage Irs2 in energy homeostasis regulation and identify potential inflammatory processes that can be targeted to treat obesity and insulin resistance.