Mineralocorticoid receptor antagonists (MRAs) are recommended for the treatment of heart failure and hypertension, mainly due to their natriuretic and anti‐fibrotic mode of action. Rodent studies have shown that MRAs can prevent adverse metabolic consequences of obesity but an elucidation of underlying molecular mechanisms is missing. Here, we investigated metabolic effects of the novel non‐steroidal MRA finerenone (FIN) in a mouse model of high‐fat diet (HFD)‐induced obesity and the signaling pathways activated by MR antagonism at level of interscapular brown adipose tissue (iBAT). C57BL/6J male mice were fed a normal diet or a HFD (with60% kcal from fat) containing or not FIN for 3 months. Metabolic parameters, adipose tissue morphology, gene and protein expression analysis were assessed. We also used brown adipocyte cultures (T37i cells) to investigate the effects of FIN‐mediated MR antagonism upon lipid and mitochondrial metabolism. HFD + FIN‐treated mice showed improved glucose tolerance together with increased multilocularity and higher expression of thermogenic markers at the level of iBAT, without differences in white adipose depots, suggesting an iBAT‐specific effect of FIN. Mechanistically, FIN increased activation of AMP‐activated protein kinase which, in turn, stimulated adipose triglyceride lipase activation, with subsequent increased expression of uncoupling protein‐1 in brown adipocytes.

中文翻译：

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新型非甾体MR拮抗剂finerenone改善高脂饮食喂养小鼠的代谢参数并通过AMPK-ATGL途径激活棕色脂肪组织

盐皮质激素受体拮抗剂 (MRA) 被推荐用于治疗心力衰竭和高血压，主要是因为它们具有利钠和抗纤维化作用。啮齿动物研究表明，MRAs 可以预防肥胖的不良代谢后果，但缺乏对潜在分子机制的阐明。在这里，我们研究了新型非甾体 MRA 细烯酮 (FIN) 在高脂饮食 (HFD) 诱导肥胖的小鼠模型中的代谢作用，以及在肩胛间棕色脂肪组织 (iBAT) 水平上由 MR 拮抗作用激活的信号通路. C57BL/6J 雄性小鼠喂食正常饮食或含有或不含 FIN 的 HFD（含 60% kcal 脂肪）3 个月。评估了代谢参数、脂肪组织形态、基因和蛋白质表达分析。我们还使用棕色脂肪细胞培养物（T37i 细胞）来研究 FIN 介导的 MR 拮抗作用对脂质和线粒体代谢的影响。HFD + FIN 处理的小鼠显示出改善的葡萄糖耐量以及 iBAT 水平的多房性增加和产热标记物的更高表达，白色脂肪库没有差异，表明 FIN 具有 iBAT 特异性作用。从机制上讲，FIN 增加了 AMP 激活的蛋白激酶的激活，进而刺激了脂肪甘油三酯脂肪酶的激活，随后棕色脂肪细胞中解偶联蛋白-1 的表达增加。HFD + FIN 处理的小鼠显示出改善的葡萄糖耐量以及 iBAT 水平的多房性增加和产热标记物的更高表达，白色脂肪库没有差异，表明 FIN 具有 iBAT 特异性作用。从机制上讲，FIN 增加了 AMP 激活的蛋白激酶的激活，进而刺激了脂肪甘油三酯脂肪酶的激活，随后棕色脂肪细胞中解偶联蛋白-1 的表达增加。HFD + FIN 处理的小鼠显示出改善的葡萄糖耐量以及 iBAT 水平的多房性增加和产热标记物的更高表达，白色脂肪库没有差异，表明 FIN 具有 iBAT 特异性作用。从机制上讲，FIN 增加了 AMP 激活的蛋白激酶的激活，进而刺激了脂肪甘油三酯脂肪酶的激活，随后棕色脂肪细胞中解偶联蛋白-1 的表达增加。