LT175 is a novel PPARα/γ ligand with potent insulin-sensitizing effects and reduced adipogenic properties.

Details

Serval ID
serval:BIB_603ECB8C465B
Type
Article: article from journal or magazin.
Collection
Publications
Title
LT175 is a novel PPARα/γ ligand with potent insulin-sensitizing effects and reduced adipogenic properties.
Journal
Journal of Biological Chemistry
Author(s)
Gilardi F., Giudici M., Mitro N., Maschi O., Guerrini U., Rando G., Maggi A., Cermenati G., Laghezza A., Loiodice F., Pochetti G., Lavecchia A., Caruso D., De Fabiani E., Bamberg K., Crestani M.
ISSN
1083-351X (Electronic)
ISSN-L
0021-9258
Publication state
Published
Issued date
2014
Peer-reviewed
Oui
Volume
289
Number
10
Pages
6908-6920
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Abstract
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.
Keywords
3T3-L1 Cells, Adipogenesis/drug effects, Animals, Biphenyl Compounds/administration & dosage, Biphenyl Compounds/metabolism, Blood Glucose/drug effects, Body Weight/drug effects, Diabetes Mellitus, Type 2/drug therapy, Dyslipidemias/drug therapy, Glucose/metabolism, Glucose Tolerance Test, Hypoglycemic Agents/metabolism, Hypoglycemic Agents/pharmacology, Insulin/blood, Insulin/pharmacology, Insulin Resistance, Ligands, Lipid Metabolism/drug effects, Male, Mice, Mice, Inbred C57BL, Nuclear Receptor Co-Repressor 1/metabolism, PPAR alpha/agonists, PPAR alpha/metabolism, PPAR gamma/agonists, PPAR gamma/metabolism, Phenylpropionates/administration & dosage, Phenylpropionates/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
15/02/2015 21:35
Last modification date
17/02/2020 17:32
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