FMOC-L-Leucine (F-L-Leu) is a chemically distinct PPARγ ligand. Two molecules of F-L-Leu bind to the ligand binding domain of a single PPARγ molecule, making its mode of receptor interaction distinct from that of other nuclear receptor ligands. F-L-Leu induces a particular allosteric configuration of PPARγ, resulting in differential cofactor recruitment and translating in distinct pharmacological properties. F-L-Leu activates PPARγ with a lower potency, but a similar maximal efficacy, than rosiglitazone. The particular PPARγ configuration induced by F-L-Leu leads to a modified pattern of target gene activation. F-L-Leu improves insulin sensitivity in normal, dietinduced glucose-intolerant, and in diabetic db/db mice, yet it has a lower adipogenic activity. These biological effects suggest that F-L-Leu is a selective PPARγ modulator that activates some (insulin sensitization), but not all (adipogenesis), PPARγ-signaling pathways.