Irisin promotes intestinal epithelial cell proliferation via Wnt/β-catenin and focal adhesion kinase signaling pathways

The regeneration of epithelia is crucial for maintaining intestinal homeostasis. Irisin is an exercise-induced hormone originally found to be secreted by skeletal muscles, thereby regulating energy metabolism. Recent studies have revealed that irisin protected against gut inflammation. However, the direct effects of irisin on the intestinal epithelial cells remain to be elucidated. In this study, mouse intestinal organoids were used to assess the effects of irisin on the proliferation of the intestinal epithelial cells. At a concentration of 100 ng/mL irisin significantly increased the growth of the intestinal organoids and upregulated the Wnt/β-catenin and focal adhesion kinase (FAK) signaling pathway genes. Notably, a FAK inhibitor 14 blocked the effects of irisin on the proliferation of the intestinal epithelial cells by inhibiting FAK phosphorylation, as well as the expressions of Wnt target genes. Furthermore, irisin (100 ng/mL) improved the recovery of the intestinal organoids from cellular damages caused by TNF-α, and markedly increased the expression of Wnt target genes in the intestinal epithelial cells. Taken together, irisin activates Wnt/β-catenin and FAK signaling pathways in the intestinal epithelial cells, thereby promoting intestinal epithelial self-renewal under normal homeostatic conditions and intestinal epithelial regeneration upon damages.