A unique PPARgamma ligand with potent insulin-sensitizing yet weak adipogenic activity.
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.
Rocchi
S
S
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 67404 Illkirch, France.
Picard
F
F
Vamecq
J
J
Gelman
L
L
Potier
N
N
Zeyer
D
D
Dubuquoy
L
L
Bac
P
P
Champy
M F
MF
Plunket
K D
KD
Leesnitzer
L M
LM
Blanchard
S G
SG
Desreumaux
P
P
Moras
D
D
Renaud
J P
JP
Auwerx
J
J
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
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