LT175, a dual PPAR ligand, increases energy metabolism and improves the diabetic phenotype in different mouse models

The nuclear receptors peroxisome proliferator-activated receptors (PPARs) play a key role in the regulation of lipid and glucose metabolism. In cell-based transactivation assay LT175 activates both PPARα and PPARγ. To investigate the mechanism of action of this compound, we studied the coregulator recruitment by FRET, which revealed that LT175 is a full PPARα and a partial PPARγ agonist. We tested the biological activity of LT175 in mouse adipocytes, showing a less adipogenic activity than rosiglitazone, a full PPARγ agonist. By using PPRE-LUC reporter mice we showed that LT175 switches on the PPAR-dependent transcription program in typical target tissues. Data obtained by RT-QPCR in diet induced obese (DIO) and db/db mice show that LT175 enhances the expression of PPAR target genes in the liver and adipose tissue. Interestingly, LT175 increases brown fat mass, contributing to decrease body weight via fat burning. LT175 ameliorates the metabolic profile and insulin sensitivity in DIO mice. These results indicate that LT175 has favourable effects on glucose and lipid metabolism and could be explored for the treatment of diabetes and obesity. Funded by Fondazione CARIPLO 2008.2511