Skeletal muscle-derived exosomal miR-146a-5p inhibits lipogenesis by mediating muscle-fat axis and targeting GDF5-PPARγsignaling

AbstractSkeletal 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 new mediator in the inter-tissue communication still remains unclear. Recently, we discovered that miR-146a-5p was mainly enriched in skeletal muscle-derived exosomes (SKM-Exos), more 50-fold higher than fat exosomes. Here, we investigated the role of skeletal muscle-derived exosome regulating lipid metabolism in adipose tissue by delivering miR-146a-5p. The results showed that exosomes from skeletal myoblast significantly inhibited the differentiation of preadipocytes and its 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) significantly increased body weight gain and decreased oxidative metabolism in mice. Whereas the internalization of this miRNA into the mKO mice by injecting skeletal muscle-derived exosomes from the Flox mice (Flox-Exos) resulted in the significant phenotypic reversion, including down-regulation of genes and proteins involved in fat synthesis. Mechanistically, miR-146a-5p has also been demonstrated to function as a negative regulator of peroxisome proliferator-activated receptor γ (PPARγ) signaling by directly targeting growth and differentiation factor 5 (GDF5) gene to mediate fat synthesis 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 lipogenesis and obesity via mediating the skeletal muscle-fat signaling axis, and may serve as a target for the development of therapies against various metabolic diseases, including obesity, lipodystrophy and insulin resistance.