Nitroalkene derivatives of linoleic acid (nitrolinoleic acid, LNO₂) are formed via nitric oxide-dependent oxidative inflammatory reactions and are found at concentrations of ≈500 nM in the blood of healthy individuals. We report that LNO₂ is a potent endogenous ligand for peroxisome proliferator-activated receptor γ (PPARγ; K_i ≈133 nM) that acts within physiological concentration ranges. This nuclear hormone receptor (PPARγ) regulates glucose homeostasis, lipid metabolism, and inflammation. PPARγ ligand activity is specific for LNO₂ and not mediated by LNO₂ decay products, NO donors, linoleic acid (LA), or oxidized LA. LNO₂ is a significantly more robust PPARγ ligand than other reported endogenous PPARγ ligands, including lysophosphatidic acid (16:0 and 18:1), 15-deoxy-Δ^12,14-PGJ₂, conjugated LA and azelaoyl-phosphocholine. LNO₂ activation of PPARγ via CV-1 cell luciferase reporter gene expression analysis revealed a ligand activity that rivals or exceeds synthetic PPARγ agonists such as rosiglitazone and ciglitazone, is coactivated by 9 cis-retinoic acid and is inhibited by the PPARγ antagonist GW9662. LNO₂ induces PPARγ-dependent macrophage CD-36 expression, adipocyte differentiation, and glucose uptake also at a potency rivaling thiazolidinediones. These observations reveal that NO-mediated cell signaling reactions can be transduced by fatty acid nitration products and PPAR-dependent gene expression.