Irisin Exerts Inhibitory Effect on Adipogenesis Through Regulation of Wnt Signaling

Abstract

Irisin is an exercise-induced myokine known to induce adipocyte browning through induction of uncoupling protein 1. Recent studies have reported that irisin is also an adipokine. However, there is limiting evidence on the role of endogenous irisin from adipocytes. In this study we aim to elucidate the expression and secretion pattern of irisin during adipocyte differentiation and the role of endogenous and exogenous irisin on the adipogenic process. As such, recombinant irisin, plasmid expressing FNDC5 and small interfering RNA were utilized. Our results show that the gene expression of irisin precursor FNDC5 and irisin secretion increases at the early stage of adipogenesis. Both recombinant irisin treated cells and FNDC5-overexpressed cells resulted in inhibition of adipogenesis evidenced by downregulated C/EBPα, PPARγ, and FABP4 expression and reduced lipid accumulation. Further data showed that the inhibitory effect of irisin on adipogenesis is mediated though potentiation of Wnt expression, which is known to determine the fate of mesenchymal stem cells and regulate adipogenesis. Conversely, FNDC5 knockdown cells showed downregulated Wnt expression, but failed to further induce adipogenesis. This study suggests that both exogenous and endogenous irisin is able to inhibit adipogenesis and that activation of Wnt and subsequent repression of transcription factors is partly involved in this process. This provides a novel insight on the local effect of irisin on adipocytes and additional benefit to protect against obesity-related metabolic disorders.

New insights into the cellular activities of Fndc5/Irisin and its signaling pathways

“…Therefore, besides of the main role of irisin which is browning of WAT, irisin also prohibits accumulation of lipids through up-regulation of adipose triglyceride lipase (ATGL) and down regulation of fatty acid synthase (FAS) [41]. This modulatory effect is mediated by the PPARγ, C/EBPa, and FABP4 axis under control of Wnt signaling, as FNDC5/irisin up regulates Wnt6 and Wnt10a and Wnt 10b [42]. Wnt signaling is inhibitory for adipocyte differentiation [43].…”

Recombinant Irisin Prevents the Reduction of Osteoblast Differentiation Induced by Stimulated Microgravity through Increasing β-Catenin Expression

“…To investigate the mechanism underlying how r-irisin increased osteoblast differentiation, we analyzed signaling pathways which irisin regulated based on reported studies, and found that irisin could modulate Notch [43], focal adhesion kinase (FAK) -extracellular signal-regulated kinase (Erk) -mitogen-activated protein (MAP) [23,25,44,45], reactive oxygen species (ROS) [46,47], phosphatidylinositol-3-kinase (PI3K) -v-akt murine thymoma viral oncogene homolog 1(AKT) [48], and Wnt/β-catenin [27,37,45] signaling pathways. Significantly, it is reported that irisin inhibited adipogenesis through regulating the Wnt/β-catenin signaling pathway [37]. In addition, Wnt antagonists sclerostin and dickkopf-1 were downregulated in MLO-Y4 cells after treatment with r-irisin [45].…”

“…Irisin was reported to exert inhibitory effect on adipogenesis through regulating the Wnt/β-catenin signaling pathway [37], which is a key signaling pathway in controlling osteoblast differentiation and bone formation [38]. Colaianni et al demonstrated that r-irisin could increase β-catenin expression during differentiation of bone marrow stromal cells [27].…”

“…In osteoblasts, mechanical stimulation causes a rapid, transient accumulation of active β-catenin in the cytoplasm and its translocation into the nucleus [34,35], and β-catenin is also sensitive to simulated microgravity [14,36]. It was reported that irisin influences adipogenesis through regulating the Wnt/β-catenin signaling pathway [37], and it increases β-catenin expression during osteogenic differentiation [27]. These findings bring up an intriguing possibility that irisin may be involved in the process of osteoblast differentiation through altering β-catenin under simulated microgravity condition.…”

Irisin in Liver Cirrhosis

“…Irisin is a recently identified myokine, which is mainly expressed and secreted by skeletal muscles as a cleavage product of fibronectin type III domain containing 5 (FNDC5) [ 14 ]. Furthermore, irisin is produced by adipose tissue; therefore, it seems to function as a myokine as well as an adipokine [ 15 , 16 , 17 ]. The regulation of irisin levels is dependent on PPAR-γ (peroxisome proliferator-activated receptor gamma) coactivator-1-α (PGC1α).…”