The NLRP3-inflammasome complex has emerged as an important component of inflammatory processes in metabolic dysfunction induced by high-caloric diets. In this study, we investigate the molecular mechanisms by which NLRP3 inhibition may attenuate diet-induced cardiac injury. Here we show the cardiac damage induced by high sugar diet (HSD), high fat diet (HFD) or high sugar/fat diet (HSFD) over 15 weeks. Genetic ablation of NLRP3 protected against this damage by autophagy induction and apoptotic control. Furthermore, NLRP3 inhibition by the selective small molecule MCC950 resulted in similar autophagy induction and apoptotic control in hearts after diets. These data were reproduced in THP-1 cells treated with MCC950 and cultured in media supplemented with serum from mice dosed with MCC950 and fed with diets. NLRP3 inhibition exerted beneficial metabolic, and autophagic adaptations in hearts from obesogenic diets. The inhibition of NLRP3 activation may hold promise in the treatment of metabolic and cardiovascular diseases.
Aging is the major risk factor for many metabolic chronic diseases. Several metabolic pathways suffer a progressive impairment during aging including body composition and insulin resistance which are associated to autophagy dysfunction and increased inflammation. Many of these alterations are aggravated by non-healthy lifestyle such as obesity and hypercaloric diet which have been shown to accelerate aging. Here, we show that the deleterious effect of hypercaloric diets is reverted by the NLRP3 inflammasome inhibition. NLRP3 deficiency extends mean lifespan of adult mice fed a high-fat diet. This lifespan extension is accompanied by metabolic health benefits including reduced liver steatosis and cardiac damage, improved glucose and lipid metabolism, and improved protein expression profiles of SIRT-1, mTOR, autophagic flux, and apoptosis. These findings suggest that the suppression of NLRP3 prevented many age-associated changes in metabolism impaired by the effect of hypercaloric diets.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.