Eplerenone prevented obesity-induced inflammasome activation and glucose intolerance.
Obesity-associated activation of the renin-angiotensin-aldosterone system is implicated in the pathogenesis of insulin resistance; however, influences of mineralocorticoid receptor (MR) inhibition remain unclear. Therefore, we aimed to clarify the anti-inflammatory mechanisms of MR inhibition using eplerenone, a selective MR antagonist, in C57BL/6 mice fed a high-fat diet (HFD) for 12 weeks. Eplerenone prevented excessive body weight gain and fat accumulation, ameliorated glucose intolerance and insulin resistance and enhanced energy metabolism. In the epididymal white adipose tissue (eWAT), eplerenone prevented obesity-induced accumulation of F4/80+CD11c+CD206--M1-adipose tissue macrophage (ATM) and reduction of F4/80+CD11c-CD206+-M2-ATM. Interestingly, M1-macrophage exhibited lower expression levels of MR, compared with M2-macrophage, in the ATM of eWAT and in vitro-polarized bone marrow-derived macrophages (BMDM). Importantly, eplerenone and MR knockdown attenuated the increase in the expression levels of proIl1b, Il6 and Tnfa, in the eWAT and liver of HFD-fed mice and LPS-stimulated BMDM. Moreover, eplerenone suppressed IL1b secretion from eWAT of HFD-fed mice. To reveal the anti-inflammatory mechanism, we investigated the involvement of NLRP3-inflammasome activation, a key process of IL1b overproduction. Eplerenone suppressed the expression of the inflammasome components, Nlrp3 and Caspase1, in the eWAT and liver. Concerning the second triggering factors, ROS production and ATP- and nigericin-induced IL1b secretion were suppressed by eplerenone in the LPS-primed BMDM. These results indicate that eplerenone inhibited both the priming and triggering signals that promote NLRP3-inflammasome activation. Therefore, we consider MR to be a crucial target to prevent metabolic disorders by suppressing inflammasome-mediated chronic inflammation in the adipose tissue and liver under obese conditions.
['Wada|Tsutomu|T|', 'Ishikawa|Akari|A|', 'Watanabe|Eri|E|', 'Nakamura|Yuto|Y|', 'Aruga|Yusuke|Y|', 'Hasegawa|Hayate|H|', 'Onogi|Yasuhiro|Y|', 'Honda|Hiroe|H|', 'Nagai|Yoshinori|Y|', 'Takatsu|Kiyoshi|K|', 'Ishii|Yoko|Y|', 'Sasahara|Masakiyo|M|', 'Koya|Daisuke|D|', 'Tsuneki|Hiroshi|H|', 'Sasaoka|Toshiyasu|T|']
D052436:Adipose Tissue, White D000818:Animals D016207:Cytokines D059305:Diet, High-Fat D004353:Drug Evaluation, Preclinical D004734:Energy Metabolism D000077545:Eplerenone D018149:Glucose Intolerance D058847:Inflammasomes D007249:Inflammation D008099:Liver D008264:Macrophages D008297:Male D008810:Mice, Inbred C57BL D000451:Mineralocorticoid Receptor Antagonists D000071199:NLR Family, Pyrin Domain-Containing 3 Protein D009765:Obesity D017382:Reactive Oxygen Species D018161:Receptors, Mineralocorticoid D013148:Spironolactone
mineralocorticoid receptor NLRP3 inflammasome, adipose tissue macrophage glucose metabolism renin-angiotensin system