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LT175 is a novel PPARα/γ ligand with potent insulin-sensitizing effects and reduced adipogenic properties.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2014 Mar 07; Vol. 289 (10), pp. 6908-6920. Date of Electronic Publication: 2014 Jan 22. - Publication Year :
- 2014
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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.
- Subjects :
- 3T3-L1 Cells
Animals
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
Insulin blood
Ligands
Lipid Metabolism drug effects
Male
Mice
Mice, Inbred C57BL
Nuclear Receptor Co-Repressor 1 metabolism
PPAR alpha metabolism
PPAR gamma metabolism
Phenylpropionates metabolism
Adipogenesis drug effects
Biphenyl Compounds administration & dosage
Hypoglycemic Agents pharmacology
Insulin pharmacology
Insulin Resistance
PPAR alpha agonists
PPAR gamma agonists
Phenylpropionates administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 289
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 24451380
- Full Text :
- https://doi.org/10.1074/jbc.M113.506394