LT175 is a novel PPARα/γ ligand with potent insulin-sensitizing effects and reduced adipogenic properties.
Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors regulating lipid and glucose metabolism. Ongoing drug discovery programs aim to develop dual PPARα/γ agonists devoid of the side effects of the marketed antidiabetic agents thiazolidinediones and the dual agonists glitazars. Recently, we described a new dual PPARα/γ ligand, LT175, with a partial agonist profile against PPARγ and interacting with a newly identified region of the PPARγ-ligand binding domain (1). Here we show that LT175 differentially activated PPARγ target genes involved in fatty acid esterification and storage in 3T3-L1-derived adipocytes. This resulted in a less severe lipid accumulation compared with that triggered by rosiglitazone, suggesting that LT175 may have a lower adipogenic activity. Consistent with this hypothesis, in vivo administration of LT175 to mice fed a high-fat diet decreased body weight, adipocyte size, and white adipose tissue mass, as assessed by magnetic resonance imaging. Furthermore, LT175 significantly reduced plasma glucose, insulin, non-esterified fatty acids, triglycerides, and cholesterol and increased circulating adiponectin and fibroblast growth factor 21 levels. Oral glucose and insulin tolerance tests showed that the compound improves glucose homeostasis and insulin sensitivity. Moreover, we demonstrate that the peculiar interaction of LT175 with PPARγ affected the recruitment of the coregulators cyclic-AMP response element-binding protein-binding protein and nuclear corepressor 1 (NCoR1), fundamentals for the PPARγ-mediated adipogenic program. In conclusion, our results describe a new PPAR ligand, modulating lipid and glucose metabolism with reduced adipogenic activity, that may be used as a model for a series of novel molecules with an improved pharmacological profile for the treatment of dyslipidemia and type 2 diabetes.
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milan, Italy.
Federica
F
Gilardi
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milan, Italy.
Marco
M
Giudici
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milan, Italy.
Nico
N
Mitro
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milan, Italy.
Omar
O
Maschi
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milan, Italy.
Uliano
U
Guerrini
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milan, Italy.
Gianpaolo
G
Rando
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milan, Italy.
Adriana
A
Maggi
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milan, Italy.
Gaia
G
Cermenati
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", 70125 Bari, Italy.
Antonio
A
Laghezza
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", 70125 Bari, Italy.
Fulvio
F
Loiodice
Consiglio Nazionale delle Ricerche (CNR), 00016 Montelibretti, Rome, Italy.
Giorgio
G
Pochetti
Dipartimento di Farmacia, "Drug Discovery" Laboratory, Università degli Studi di Napoli "Federico II", 80131 Naples, Italy.
Antonio
A
Lavecchia
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milan, Italy.
Donatella
D
Caruso
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milan, Italy.
Emma
E
De Fabiani
AstraZeneca, 431 83 Mölndal, Sweden.
Krister
K
Bamberg
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milan, Italy. Electronic address: maurizio.crestani@unimi.it.
Maurizio
M
Crestani
D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000378:metabolism; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D050171:Dyslipidemias / Q000188:drug therapy; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D007333:Insulin Resistance; D008024:Ligands; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D010666:Phenylpropionates / Q000008:administration & dosage* / Q000378:metabolism
C000589034:2-(4-phenylphenoxy)-3-phenylpropanoic acid; D001713:Biphenyl Compounds; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D008024:Ligands; C539128:Ncor1 protein, mouse; D056971:Nuclear Receptor Co-Repressor 1; D047493:PPAR alpha; D047495:PPAR gamma; D010666:Phenylpropionates; D005947:Glucose
Adipogenesis; Glucose Metabolism; Insulin Resistance; Metabolic Regulation; Peroxisome Proliferator-activated Receptor (PPAR); Transcription Coregulators; Type 2 Diabetes