MicroRNA miR-222 mediates pioglitazone beneficial effects on skeletal muscle of diet-induced obese mice
MicroRNA miR-222 mediates pioglitazone beneficial effects on skeletal muscle of diet-induced obese mice
复制标题
DOI：
10.1016/j.mce.2019.110661
复制
发表时间：
2020-02-05
影响因子：
4.1
通讯作者：
Rodrigues, Alice C.
中科院分区：
文献类型：
--
作者：
de Mendonca, Mariana;de Sousa, Erica;Rodrigues, Alice C.
吡格列酮属于噻唑烷二酮类药物 (TZD) 类，是一种口服降血糖药物，用于治疗 2 型糖尿病，可改善靶组织的胰岛素敏感性。脂肪组织是吡格列酮（PPARg 和 PPARa 激动剂）的主要靶点；然而，研究也指出骨骼肌是一个目标。 TZD 的非 PPAR 靶点已被描述，因此我们旨在研究吡格列酮对骨骼肌的直接影响以及 microRNA 作为该药物靶点的可能作用。由于脂肪酸氧化和线粒体活性增加，吡格列酮治疗肥胖小鼠增加了胰岛素介导的葡萄糖转运。 GW9662 治疗的 PPARg 阻断消除了吡格列酮对肥胖小鼠全身和肌肉胰岛素敏感性以及柠檬酸合酶活性的影响。高脂肪饮食八周后，各组比目鱼肌中的 miR-221-3p 表达相似，与对照组相比，肥胖小鼠中 miR-23b-3p 和 miR-222-3p 表达上调，吡格列酮治疗能够逆转这种情况。 C2C12 细胞的体外研究表明，抑制 miR-222-3p 可保护 C2C12 细胞免受胰岛素抵抗和棕榈酸酯诱导的非线粒体呼吸增加。总之，这些数据证明了吡格列酮在不依赖于 PPARg 的 microRNA 下调中的作用。此外，miR-222可能是一种新的不依赖于PPARg的机制，吡格列酮通过该机制改善骨骼肌的胰岛素敏感性。
Pioglitazone belongs to the class of drugs thiazolidinediones (TZDs) and is an oral hypoglycemic drug, used in the treatment of type 2 diabetes, which improves insulin sensitivity in target tissues. Adipose tissue is the main target of pioglitazone, a PPARg and PPARa agonist; however, studies also point to skeletal muscle as a target. Non-PPAR targets of TZDs have been described, thus we aimed to study the direct effects of pioglitazone on skeletal muscle and the possible role of microRNAs as targets of this drug. Pioglitazone treatment of obese mice increased insulin-mediated glucose transport as a result of increased fatty acid oxidation and mitochondrial activity. PPARg blockage by treatment with GW9662 nullified pioglitazone's effect on systemic and muscle insulin sensitivity and citrate synthase activity of obese mice. After eight weeks of high-fat diet, miR-221-3p expression in soleus muscle was similar among the groups and miR-23b-3p and miR-222-3p were up-regulated in obese mice compared to the control group, and treatment with pioglitazone was able to reverse this condition. In vitro studies in C2C12 cells suggest that inhibition of miR-222-3p protects C2C12 cells from insulin resistance and increased non-mitochondrial respiration induced by palmitate. Together, these data demonstrate a role of pioglitazone in the downregulation of microRNAs that is not dependent on PPARg. Moreover, miR-222 may be a novel PPARg-independent mechanism through which pioglitazone improves insulin sensitivity in skeletal muscle.