FMOC-L-Leucine (F-L-Leu) is a chemically distinct PPAR gamma ligand. Two mo
lecules 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 ot
her nuclear receptor ligands. F-L-Leu induces a particular allosteric confi
guration 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 rosiglitaz
one. The particular PPAR gamma configuration induced by F-L-Leu leads to a
modified pattern of target gene activation. F-L-Leu improves insulin sensit
ivity in normal, diet-induced glucose-intolerant, and in diabetic db/db mic
e, yet it has a lower adipogenic activity. These biological effects suggest
that F-L-Leu is a selective PPAR gamma modulator that activates some (insu
lin sensitization), but not all (adipogenesis), PPAR gamma -signaling pathw
ays.