AUTHOR=Sokolova Marina , Sjaastad Ivar , Louwe Mieke C. , Alfsnes Katrine , Aronsen Jan Magnus , Zhang Lili , Haugstad Solveig B. , Bendiksen Bård Andre , Øgaard Jonas , Bliksøen Marte , Lien Egil , Berge Rolf K. , Aukrust Pål , Ranheim Trine , Yndestad Arne 

TITLE=NLRP3 Inflammasome Promotes Myocardial Remodeling During Diet-Induced Obesity

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.01621

DOI=10.3389/fimmu.2019.01621

ISSN=1664-3224

ABSTRACT=<p><bold>Background:</bold> Obesity is an increasingly prevalent metabolic disorder in the modern world and is associated with structural and functional changes in the heart. The NLRP3 inflammasome is an innate immune sensor that can be activated in response to endogenous danger signals and triggers activation of interleukin (IL)-1β and IL-18. Increasing evidence points to the involvement of the NLRP3 inflammasome in obesity-induced inflammation and insulin resistance, and we hypothesized that it also could play a role in the development of obesity induced cardiac alterations.</p><p><bold>Methods and Results:</bold> WT, <italic>Nlrp3</italic><sup>−/−</sup>, and <italic>ASC</italic><sup>−/−</sup> (<italic>Pycard</italic><sup>−/−</sup>) male mice were exposed to high fat diet (HFD; 60 cal% fat) or control diet for 52 weeks. Cardiac structure and function were evaluated by echocardiography and magnetic resonance imaging, respectively. Whereas, NLRP3 and ASC deficiency did not affect the cardiac hypertrophic response to obesity, it was preventive against left ventricle concentric remodeling and impairment of diastolic function. Furthermore, whereas NLRP3 and ASC deficiency attenuated systemic inflammation in HFD fed mice; long-term HFD did not induce significant cardiac fibrosis or inflammation, suggesting that the beneficial effects of NLRP3 inflammasome deficiency on myocardial remodeling at least partly reflect systemic mechanisms. <italic>Nlrp3</italic> and <italic>ASC</italic> (<italic>Pycard</italic>) deficient mice were also protected against obesity-induced systemic metabolic dysregulation, as well as lipid accumulation and impaired insulin signaling in hepatic and cardiac tissues.</p><p><bold>Conclusions:</bold> Our data indicate that the NLRP3 inflammasome modulates cardiac concentric remodeling in obesity through effects on systemic inflammation and metabolic disturbances, with effect on insulin signaling as a potential mediator within the myocardium.</p>