Abstract 609: Pharmacological Inhibition of NLRP3 Inflammasome by Parthenolide Improves Obesity-Induced Insulin Resistance in Diet-Induced Obese Mice

Abstract

Many landmark studies have reported the Nod-like receptor proteins containing Pyrin domain (NLRP3) inflammasome activation in metabolic diseases that include obesity, atherosclerosis and type 2 diabetes. Therefore, the present study was aimed: (i) to determine the role of NLRP3 in inflammation and insulin resistance in high fat diet-induced obesity (DIO) model of mice, and (ii) to determine whether parthenolide, a NLRP3 inhibitor, is able to protect mice against inflammation and insulin resistance in high fat DIO model. METHODS: Lipopolysaccharide (1 ng/ml) primed mouse intraperitoneal macrophages were treated with Parthenolide (0.1 to 30 μM) to evaluate its effect on TNF-α and IL-1β. Parthenolide and Pioglitazone were administered to DIO mice (fed 60% high fat diet) at 5 and 30 mg/kg QD, PO, respectively for 60 days to evaluate their effect on insulin resistance. RESULTS: Parthenolide (5 mg/kg) markedly attenuated inflammatory cytokines as evidenced by significant and dose dependant inhibition of both TNF-α and IL-1β in LPS primed macrophages. Treatment also lowered the fed blood glucose from day 14 to the entire course of study supporting the hypothesis that attenuating inflammation would be a possible intervention to insulin resistance. Parthenolide also improved peripheral insulin resistance, as demonstrated by insulin tolerance test and a significant improvement in the glucose intolerance as demonstrated by the oral glucose tolerance test. Moreover, treatment lowered plasma insulin levels indicating a trend in the improvement in insulin sensitivity. CONCLUSIONS: Collectively, obtained results support our hypothesis that Parthenolide, an inflammasome inhibitor, could be a useful agent in antagonizing obesity-induced insulin resistance