Adiponectin upregulates irisin expression through the APPL1/p38MAPK/PGC-1α signalling pathway in murine skeletal muscle

Adiponectin and irisin regulate energy homeostasis and interact with Peroxisome Proliferator-activated Receptor coactivator 1α (PGC-1α). However, whether they establish a signal connection via PGC-1α is unclear. In the current study, the expression of irisin was significantly decreased in the skeletal muscle of Adiponectin knockout (KO) mice, accompanied by a de crease in APPL1/p38 mitogen-activated protein kinase (MAPK)/PGC-1α. However, Adiponectin administration reversed this effect. In vitro, the p38 MAPK/PGC-1α signalling pathway mediated adiponectin-induced FNDC5 expression and irisin release in mouse-derived C2C12 myotube cells. Moreover, obesity caused dysregulation of the Adiponectin/APPL1/p38 MAPK/PGC-1α signalling pathway in murine skeletal muscle, ultimately inhibiting irisin synthesis and secretion; meanwhile, prolonged exercise or exogenous recombinant Adiponectin intervention activated this pathway in mouse skeletal muscle. This corresponded with an apparent improvement in high-fat diet-induced Insulin resistance. The effect of mechanically stretching C2C12 myotube cells was consistent with in vivo findings. Hence, Adiponectin upregulates irisin through the APPL1/p38MAPK/PGC-1α signalling pathway in murine skeletal muscle, which may enhance Insulin sensitivity.