Department of Pharmacology, College of Basic Medical Sciences, School of nursing, Jilin University, Changchun 130021, China.
Research Institution of Paediatrics, Department of Pediatric Endocrinology, The First Clinical Hospital Affiliated to Jilin University, Changchun, Jilin 130021, China.
Theranostics. 2018 Mar 8;8(8):2171-2188. doi: 10.7150/thno.22565. eCollection 2018.
The mechanism by which adipocyte-derived endocrine factors promote insulin resistance in skeletal muscle are not fully understood. MiR-27a is highly expressed in sera of obese individuals with prediabetes and T2DM, and mainly derived by adipose tissues. Thus, miR-27a secreted into circulation by adipose tissue may regulate insulin resistance in skeletal muscle. The association between miR-27a and insulin resistance in skeletal muscle was determined in obese children, high-fat diet-induced miR-27a knockdown obese mice, db/db mice and C2C12 cells overexpressing miR-27a. The crosstalk mediated by exosomal miR-27a between adipose tissue and skeletal muscle was determined in C2C12 cells incubated with conditioned medium prepared from palmitate-treated 3T3-L1 adipocytes. We showed that serum miR-27a level correlated positively with obesity and insulin resistance in obese children, and that elevated serum miR-27a levels correlated with insulin resistance in leptin receptor-deficient db/db mice, and with obesity and insulin resistance in high-fat diet-fed C57BL/6J mice. MiR-27a released from adipocytes of high-fat diet-fed C57BL/6J mice was associated with triglyceride accumulation. MiR-27a derived from these adipocytes induced insulin resistance in C2C12 skeletal muscle cells through miR-27a-mediated repression of PPARγ and its downstream genes involved in the development of obesity. These results identify a novel crosstalk signaling pathway between adipose tissue and skeletal muscle in the development of insulin resistance, and indicate that adipose tissue-derived miR-27a may play a key role in the development of obesity-triggered insulin resistance in skeletal muscle.
脂肪细胞衍生的内分泌因子促进骨骼肌胰岛素抵抗的机制尚不完全清楚。miR-27a 在患有前驱糖尿病和 T2DM 的肥胖个体的血清中高度表达，主要来源于脂肪组织。因此，脂肪组织分泌到循环中的 miR-27a 可能调节骨骼肌的胰岛素抵抗。在肥胖儿童、高脂肪饮食诱导的 miR-27a 敲低肥胖小鼠、db/db 小鼠和过表达 miR-27a 的 C2C12 细胞中，确定了 miR-27a 与骨骼肌胰岛素抵抗之间的关联。在用棕榈酸处理的 3T3-L1 脂肪细胞制备的条件培养基孵育的 C2C12 细胞中，确定了脂肪组织和骨骼肌之间由外泌体 miR-27a 介导的串扰。我们表明，血清 miR-27a 水平与肥胖儿童的肥胖和胰岛素抵抗呈正相关，而升高的血清 miR-27a 水平与瘦素受体缺陷型 db/db 小鼠的胰岛素抵抗以及高脂肪饮食喂养的 C57BL/6J 小鼠的肥胖和胰岛素抵抗相关。高脂肪饮食喂养的 C57BL/6J 小鼠脂肪细胞释放的 miR-27a 与甘油三酯积累有关。这些脂肪细胞衍生的 miR-27a 通过 miR-27a 介导的 PPARγ 及其下游基因的抑制，诱导 C2C12 骨骼肌细胞发生胰岛素抵抗，这些基因参与肥胖的发生。这些结果确定了胰岛素抵抗发展过程中脂肪组织和骨骼肌之间的一种新的串扰信号通路，并表明脂肪组织衍生的 miR-27a 可能在肥胖引发的骨骼肌胰岛素抵抗的发展中发挥关键作用。
