Abstract
In this work we studied the metabolic effects of the novel non-steroidal MR antagonist Finerenone (FIN) in mice fed a high-fat diet (HFD, 60% kcal as fat). We also investigated the signaling pathways underlying the beneficial metabolic effects of MR antagonism. After 3 months of HFD, mice treated with FIN showed an improvement of glucose tolerance compared to control mice as shown by intraperitoneal glucose tolerance tests. Despite this metabolic improvement, FIN-treated mice did not show a reduction in body weight compared to control mice. In order to elucidate the favourable effect of FIN on glucose tolerance we performed histological and molecular analyses at level of different adipose depots. We did not observe significant differences in classical white adipose depots (subcutaneous and visceral) between control and FIN-treated mice. Interestingly, interscapular brown adipose tissue (iBAT) of FIN-treated mice showed an increased multilocularity and a reduced size of lipid droplets, suggesting an iBAT-specific effect of FIN. We than analyzed mRNA and protein expression of uncoupling protein 1 (UCP-1) and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PCG1-alpha), showing a significant increase of both markers at iBAT level in FIN-treated mice. Furthermore, leptin and adenylate cyclase 5 (Adyc5) (specific white adipose tissue markers) mRNA expression was reduced at level of iBAT in FIN-treated mice. Finally, we demonstrated that FIN-induced MR antagonism determined an increased activation of AMP-activated protein kinase (AMPK) which, in turn, stimulated adipose triglyceride lipase (ATGL) activity, with subsequent up-regulation of genes involved in fatty acids oxidation, tricarboxylic acid cycle and thermogenesis, in iBAT. In summary, our study shows that FIN protects from iBAT dysfunction and improves glucose tolerance in HFD-fed mice. Importantly, FIN effects on iBAT are mediated by a MR-AMPK-ATGL-UCP-1 signaling cascade. Therefore, MR antagonism by FIN in clinical settings might offer metabolic advantages, on top of its anti-fibrotic action, in multi-morbid cardiorenal patients.