Study of the mechanism of action of LT175, a dual PPAR ligand that ameliorates the metabolic profile and insulin sensitivity in different mouse models

Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that play a key role in the regulation of lipid and glucose metabolism. Recent works aim at developing dual PPAR α/γ agonists devoid of the side effects of the antidiabetic agents thiazolidinediones and the dual-agonists glitazars. We studied the molecular mechanism of action of a new compound, LT175, and the regulation of glucose and lipid metabolism in cell and animal models. In cell-based assays LT175 activates both PPARα and PPARγ. Because of the unique structural properties of the ligand-receptor complex, we studied the coregulator recruitment by FRET, which revealed that LT175 activates both PPARα and PPARγ. Because of the unique structural properties of the ligand-receptor complex, 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 lower lipid accumulation than the PPARγ full agonist rosiglitazone, which may be explained by the lower expression of genes for fatty acid uptake (CD36) and glycerol 3-phosphate formation (PEPCK and GYK). Using PPRE-LUC reporter mice we showed that LT175 switches on the PPAR-dependent transcription program in typical target tissues. Administration of LT175 to Diet Induced Obese (DIO) mice decreases plasma glucose, insulin, Non-Esterified Fatty Acids (NEFA), triglycerides and cholesterol while it increases adiponectin and FGF21 levels, ameliorating the metabolic profile and insulin sensitivity. Data obtained by RT-qPCR in DIO and db/db mice show that LT175 enhances the expression of PPAR target genes in the liver and adipose tissue. LT175, opposite to rosiglitazone, does not increase the expression of renal sodium transporter ENaCγ, which is involved in fluid retention. These results indicate that LT175 has favourable effects on glucose and lipid metabolism with a reduction of some of the major side-effects and could therefore represent a new PPAR ligand with a more favourable profile as compared to glitazones. Supported by a grant from Fondazione Cariplo 2009.2727.