A unique PPARγ ligand with potent insulin-sensitizing yet weak adipogenic activity

FMOC-L-Leucine (F-L-Leu) is a chemically distinct PPAR gamma ligand. Two molecules of F-L-Leu bind to the ligand binding domain of a single PPAR gamma molecule, making its mode of receptor interaction distinct from that of other nuclear receptor ligands. F-L-Leu induces a particular allosteric configuration of PPAR gamma, resulting in differential cofactor recruitment and translating in distinct pharmacological properties. F-L-Leu activates PPAR gamma with a lower potency, but a similar maximal efficacy, than rosiglitazone. The particular PPAR gamma configuration induced by F-L-Leu leads to a modified pattern of target gene activation. F-L-Leu improves insulin sensitivity in normal, diet-induced 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 PPAR gamma modulator that activates some (insulin sensitization), but not all (adipogenesis), PPAR gamma -signaling pathways.