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 LNO2is a potent endogenous ligand for peroxisome proliferator-activated receptor γ (PPARγ; Ki≈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 LNO2and not mediated by LNO2decay products, NO donors, linoleic acid (LA), or oxidized LA. LNO2is a significantly more robust PPARγ ligand than other reported endogenous PPARγ ligands, including lysophosphatidic acid (16:0 and 18:1), 15-deoxy-Δ12,14- PGJ2, conjugated LA and azelaoyl-phosphocholine. LNO2activation 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. LNO2induces 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.