Abstract 1585: Coactivation of PPAR Delta Along with Alpha and Gamma is a Better Option to Regulate Metabolic Syndrome
In recent years number of people suffering from insulin resistance, diabetes, dyslipidemia, hypertension and obesity termed together as Metabolic Syndrome (MS) have increased in an epidemic proportion. PPARγ and dual α/γ agonists have shown promise in treating several of these risk factors, but there are serious concerns on side effects such as weight gain, hemodilution and heart weight increase. PPARδ has recently been reported to have beneficial effect on different metabolic parameters, cardiomyopathy and obesity. These reports gave us an impetus to explore the combination of PPARδ along with PPARα and moderate γ for the treatment of metabolic syndrome. DRL 15609, an experimental molecule was prepared with EC50 values of 0.51, 3 and 8 uM for PPARα, γand δ respectively and studied in 2 metabolic syndrome models. In Zucker fa/fa rats, a dose dependent effect with a max of 87, 68, 94 and 40% reduction in plasma triglyceride (TG), free fatty acid (FFA), Insulin (Ins) and cholesterol levels at 3 mg/kg dose after 9 days of treatment was observed. In ZDF rats after 13 days of treatment at 5 mg/kg dose 15609 showed 67, 86, 67 & 67% reduction in plasma glucose, TG, FFA & Ins respectively. Dual PPARα/β activator Muraglitazar (Mura) showed similar effect only at 30 mg/kg dose. Interestingly, in both these models 15609 also showed significant 18 & 11% reduction in systolic blood pressure after 21 days of treatment. No hemodilution or increase in body, epididymal fat or heart weight were observed with 15609 as observed with Mura or Rosiglitazone (Rosi) at their efficacy dose. In a 14 days rat study, DRL 15609 even at 50 mg/kg dose showed no increase in plasma and blood volume or body, fat or heart weight, whereas Rosi showed all adverse effects. Our data demonstrates that coactivation of PPARα along with PPAR and moderate γ can produce a robust effect on glucose, lipid, insulin resistance and hypertension without inducing the known PPAR related undesireable effects. Taken together combining PPARα with α/γ can be a better option for the treatment of metabolic syndrome.