LT175 Is a Novel PPARα/γ Ligand with Potent Insulin-sensitizing Effects and Reduced Adipogenic Properties

Background: PPARs are attractive targets of antidiabetic agents. However, PPAR ligands show side effects that hinder their clinical use. Results: LT175 improves insulin sensitivity and reduces body weight via selective gene activation in adipose tissue. Conclusion: LT175 shows an improved pharmacological profile linked to characteristic binding and differential coregulator recruitment. Significance: LT175 may be a scaffold molecule to design a safer generation of PPAR ligands. Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors regulating lipid and glucose metabolism. Ongoing drug discovery programs aim to develop dual PPAR/ agonists devoid of the side effects of the marketed antidiabetic agents thiazolidinediones and the dual agonists glitazars. Recently, we described a new dual PPAR/ ligand, LT175, with a partial agonist profile against PPAR and interacting with a newly identified region of the PPAR-ligand binding domain (1). Here we show that LT175 differentially activated PPAR 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 PPAR affected the recruitment of the coregulators cyclic-AMP response element-binding protein-binding protein and nuclear corepressor 1 (NCoR1), fundamentals for the PPAR-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.