LT175 is a novel PPAR{alpha}/{gamma} ligand with potent insulin sensitizing effects and reduced adipogenic properties [Gene Regulation]

January 22nd, 2014 by 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.

Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors regulating lipid and glucose metabolism. Ongoing drug discovery programs aim at developing dual PPARα/γ agonists devoid of the side effects of the marketed antidiabetic agents thiazolidinediones and the dual-agonists glitazars. We recently 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-LBD (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 to that triggered by rosiglitazone, suggesting that LT175 may have lower adipogenic activity. Consistent with this hypothesis, in vivo administration of LT175 to mice fed 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 show that the compound improved 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 (CREB)-binding protein (CBP) 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, which may be used as a model for a series of novel molecules with improved pharmacological profile for the treatment of dyslipidemia and type 2 diabetes.