Macrophage polarization involves a coordinated metabolic and transcriptional rewiring that is only partially understood. By using an integrated high-throughput transcriptional-metabolic profiling and analysis pipeline, we characterized systemic changes during murine macrophage M1 and M2 polarization. M2 polarization was found to activate glutamine catabolism and UDP-GlcNAc-associated modules. Correspondingly, glutamine deprivation or inhibition of N-glycosylation decreased M2 polarization and production of chemokine CCL22. In M1 macrophages, we identified a metabolic break at Idh, the enzyme that converts isocitrate to alpha-ketoglutarate, providing mechanistic explanation for TCA cycle fragmentation. 13C-tracer studies suggested the presence of an active variant of the aspartate-arginosuccinate shunt that compensated for this break. Consistently, inhibition of aspartate-aminotransferase, a key enzyme of the shunt, inhibited nitric oxide and interleukin-6 production in M1 macrophages, while promoting mitochondrial respiration. This systems approach provides a highly integrated picture of the physiological modules supporting macrophage polarization, identifying potential pharmacologic control points for both macrophage phenotypes. •Glutamine deprivation affects M2 polarization but not M1 polarization•UDP-GlcNAc biosynthesis and N-glycosylation are important for M2 polarization•There is no reverse or direct flow through Idh or malic enzyme in M1 macrophages•Aspartate-arginosuccinate shunt connects the NO and TCA cycles in M1 polarization Polarization of macrophages involves a metabolic and transcriptional rewiring that is only partially understood. Artyomov and colleagues used an integrated high-throughput transcriptional-metabolic profiling and analysis pipeline to identify metabolic modules that support macrophage polarization and function.