STAT6 interacts with PPARγ to elicit macrophage polarization towards an anti-inflammatory, insulin-sensitizing phenotype. Mice deficient in STAT6 display liver lipid accumulation (hepatosteatosis). Rosiglitazone (RSG), a PPARγ agonist, ameliorates hepatosteatosis and enhances insulin sensitivity. To elucidate the role of STAT6 in PPARγ action on hepatosteatosis we compared liver proteomes of RSG-treated wild type and STAT6-deficient mice and we identified pyruvate kinase M2 (PKM2), a glycolysis and proliferation-regulating enzyme that displayed STAT6-dependent expression. RSG induced PKM2 within inflammatory cells in liver but suppressed its expression in adipose tissue. RSG diminished hepatosteatosis and oxidative stress, enhanced fat accumulation and improved insulin sensitivity in STAT6-deficient mice. Our data reveal a complex interaction between STAT6 and PPARγ in the regulation of liver and adipose tissue lipid depot distribution and design STAT6 as a novel link between inflammatory cell metabolism and adipocyte and hepatocyte function.