title: A unique PPARgamma ligand with potent insulin-sensitizing yet weak adipogenic activity.
abstract: FMOC-L-Leucine (F-L-Leu) is a chemically distinct PPARgamma ligand. Two molecules of F-L-Leu bind to the ligand binding domain of a single PPARgamma molecule, making its mode of receptor interaction distinct from that of other nuclear receptor ligands. F-L-Leu induces a particular allosteric configuration of PPARgamma, resulting in differential cofactor recruitment and translating in distinct pharmacological properties. F-L-Leu activates PPARgamma with a lower potency, but a similar maximal efficacy, than rosiglitazone. The particular PPARgamma 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 PPARgamma modulator that activates some (insulin sensitization), but not all (adipogenesis), PPARgamma-signaling pathways.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 67404 Illkirch, France.
authors.forename: S
authors.initials: S
authors.lastname: Rocchi
authors.forename: F
authors.initials: F
authors.lastname: Picard
authors.forename: J
authors.initials: J
authors.lastname: Vamecq
authors.forename: L
authors.initials: L
authors.lastname: Gelman
authors.forename: N
authors.initials: N
authors.lastname: Potier
authors.forename: D
authors.initials: D
authors.lastname: Zeyer
authors.forename: L
authors.initials: L
authors.lastname: Dubuquoy
authors.forename: P
authors.initials: P
authors.lastname: Bac
authors.forename: M F
authors.initials: MF
authors.lastname: Champy
authors.forename: K D
authors.initials: KD
authors.lastname: Plunket
authors.forename: L M
authors.initials: LM
authors.lastname: Leesnitzer
authors.forename: S G
authors.initials: SG
authors.lastname: Blanchard
authors.forename: P
authors.initials: P
authors.lastname: Desreumaux
authors.forename: D
authors.initials: D
authors.lastname: Moras
authors.forename: J P
authors.initials: JP
authors.lastname: Renaud
authors.forename: J
authors.initials: J
authors.lastname: Auwerx
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000502:physiology*; D000596:Amino Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D002454:Cell Differentiation; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005449:Fluorenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000502:physiology; D017930:Genes, Reporter; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology; D007930:Leucine / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D000077154:Rosiglitazone; D021241:Spectrometry, Mass, Electrospray Ionization; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism
chemical_list: D000596:Amino Acids; D001786:Blood Glucose; D005449:Fluorenes; D007004:Hypoglycemic Agents; D008024:Ligands; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D014443:Tyrosine; D007930:Leucine