Esaxerenone, a selective mineralocorticoid receptor blocker, improves insulin sensitivity in mice consuming high-fat diet
Esaxerenone, a selective mineralocorticoid receptor blocker, improves insulin sensitivity in mice consuming high-fat diet
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DOI：
10.1016/j.ejphar.2022.175190
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发表时间：
2022-08-21
影响因子：
5
通讯作者：
Sata, Masataka
中科院分区：
文献类型：
--
作者：
Bavuu, Oyunbileg;Fukuda, Daiju;Sata, Masataka
背景：依沙塞隆是一种新型的非甾体选择性矿皮质激素受体（MR）阻滞剂。MR激活在心血管和代谢疾病的发展中起着至关重要的作用。在这项研究中，我们研究了艾萨克酮对小鼠各种代谢参数的影响。材料与方法：高脂饲料（HFD）喂养雄性C57BL/6小鼠，口服依沙塞隆酮（3 mg/kg/d）。饲喂正常饮食（ND）的小鼠作为对照组。葡萄糖和胰岛素耐量、血脂水平和转氨酶水平作为代谢参数进行评估。利用组织学分析评估脂肪组织中巨噬细胞的积累情况。体外实验采用3T3-L1脂肪细胞、HepG2细胞和C2C12肌管。分别用定量RT-PCR和western blotting检测基因表达和胰岛素信号传导。结果：与ND组相比，HFD组成功诱导胰岛素抵抗。依沙塞隆改善胰岛素抵抗（P < 0.05），而不改变其他代谢参数，如脂质谱。与未治疗组相比，给予艾塞酮有降低血浆转氨酶水平的趋势。在脂肪组织中，esaxenone减少巨噬细胞聚集（P < 0.05），增加脂联素和PPAR γ的表达水平。醛固酮显著降低3T3-L1脂肪细胞中PPAR γ和脂联素的表达水平。此外，醛固酮以剂量依赖性的方式减弱胰岛素诱导的3T3-L1脂肪细胞、HepG2细胞和C2C12肌管中Akt磷酸化（P < 0.01）。经艾塞酮预处理后，这些效果得到改善。结论：艾塞酮可改善hfd小鼠的胰岛素抵抗。减少炎症和改善胰岛素信号可能是艾塞酮有益作用的基础。
Background: Esaxerenone is a novel, non-steroidal selective mineralocorticoid receptor (MR) blocker. MR acti-vation plays a crucial role in the development of cardiovascular and metabolic diseases. In this study, we investigated the effects of esaxerenone on various metabolic parameters in mice. Materials and methods: Esaxerenone (3 mg/kg/day) was orally administered to high-fat diet (HFD)-fed male C57BL/6 mice. Mice fed a normal diet (ND) served as controls. Glucose and insulin tolerance, plasma lipid levels, and transaminase levels were assessed as metabolic parameters. Macrophage accumulation in the adipose tissue was evaluated using histological analysis. 3T3-L1 adipocytes, HepG2 cells, and C2C12 myotubes were used for in vitro experiments. Gene expression and insulin signaling were examined using quantitative RT-PCR and western blotting, respectively. Results: HFD successfully induced insulin resistance compared with that in ND. Esaxerenone ameliorated insulin resistance (P < 0.05) without altering other metabolic parameters, such as the lipid profile. Esaxerenone administration tended to decrease plasma transaminase levels compared with those in the non-treated group. In the adipose tissue, esaxerenone decreased macrophage accumulation (P < 0.05) and increased the expression levels of adiponectin and PPAR gamma. Aldosterone significantly decreased the expression levels of PPAR gamma and adi-ponectin in 3T3-L1 adipocytes. Furthermore, aldosterone attenuated insulin-induced Akt phosphorylation in 3T3-L1 adipocytes, HepG2 cells, and C2C12 myotubes in a dose-dependent manner (P < 0.01). These effects were ameliorated by pretreatment with esaxerenone. Conclusion: Esaxerenone ameliorated insulin resistance in HFD-fed mice. Reduction of inflammation and improvement in insulin signaling may underlie the beneficial effects of esaxerenone.