Skeletal Muscle-Derived Exosomal miR-146a-5p Inhibits Adipogenesis by Mediating Muscle-Fat Axis and Targeting GDF5-PPAR gamma Signaling

文献类型： 外文期刊

第一作者： Qin, Mengran

作者： Qin, Mengran;Xing, Lipeng;Wu, Jiahan;Wen, Shulei;Luo, Junyi;Chen, Ting;Fan, Yaotian;Zhu, Jiahao;Yang, Lekai;Liu, Jie;Xiong, Jiali;Zhu, Canjun;Wang, Songbo;Wang, Lina;Shu, Gang;Jiang, Qingyan;Zhang, Yongliang;Sun, Jiajie;Xi, Qianyun;Chen, Xingping

作者机构：

关键词： skeletal muscle; exosomes; miR-146a-5p; adipogenesis; GDF5; crosstalk; PPAR gamma

期刊名称：INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES （ 影响因子：5.6； 五年影响因子：6.2 ）

ISSN：

年卷期： 2023 年 24 卷 5 期

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收录情况： SCI

摘要： Skeletal muscle-fat interaction is essential for maintaining organismal energy homeostasis and managing obesity by secreting cytokines and exosomes, but the role of the latter as a new mediator in inter-tissue communication remains unclear. Recently, we discovered that miR-146a-5p was mainly enriched in skeletal muscle-derived exosomes (SKM-Exos), 50-fold higher than in fat exosomes. Here, we investigated the role of skeletal muscle-derived exosomes regulating lipid metabolism in adipose tissue by delivering miR-146a-5p. The results showed that skeletal muscle cell-derived exosomes significantly inhibited the differentiation of preadipocytes and their adipogenesis. When the skeletal muscle-derived exosomes co-treated adipocytes with miR-146a-5p inhibitor, this inhibition was reversed. Additionally, skeletal muscle-specific knockout miR-146a-5p (mKO) mice significantly increased body weight gain and decreased oxidative metabolism. On the other hand, the internalization of this miRNA into the mKO mice by injecting skeletal muscle-derived exosomes from the Flox mice (Flox-Exos) resulted in significant phenotypic reversion, including down-regulation of genes and proteins involved in adipogenesis. Mechanistically, miR-146a-5p has also been demonstrated to function as a negative regulator of peroxisome proliferator-activated receptor gamma (PPAR gamma) signaling by directly targeting growth and differentiation factor 5 (GDF5) gene to mediate adipogenesis and fatty acid absorption. Taken together, these data provide new insights into the role of miR-146a-5p as a novel myokine involved in the regulation of adipogenesis and obesity via mediating the skeletal muscle-fat signaling axis, which may serve as a target for the development of therapies against metabolic diseases, such as obesity.

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