A Unique PPARγ Ligand with Potent Insulin-Sensitizing yet Weak Adipogenic Activity

• Published in: Molecular cell Vol. 8; no. 4; pp. 737 - 747
• Main Authors: Rocchi, Stéphane, Picard, Frédéric, Vamecq, Joseph, Gelman, Laurent, Potier, Noelle, Zeyer, Denis, Dubuquoy, Laurent, Bac, Pierre, Champy, Marie-France, Plunket, Kelli D., Leesnitzer, Lisa M., Blanchard, Steven G., Desreumaux, Pierre, Moras, Dino, Renaud, Jean-Paul, Auwerx, Johan
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.10.2001; Cell Press
• Subjects: Analytical chemistry; Chemical Sciences
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/S1097-2765(01)00353-7

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.