Exercise Promotes Adult Hippocampal Neurogenesis and Memory Function by Attenuating Microglial Activation in Diabetic Mice

Exercise significantly decreased T2DM-induced inflammation levels and markedly promoted hippocampal neurogenesis and memory function. However, these positive effects were reversed by 10 weeks of treatment with Cyclo RGDyk, an inhibitor of irisin receptor signalling. Additionally, exercise helped reduce the M1 phenotype polarization of hippocampal microglia in diabetic mice; this effect could be reversed with Cyclo RGDyk treatment. Moreover, exercise markedly increased the levels of fibronectin type III domain-containing protein 5 (FNDC5)/irisin gene and protein while decreasing the expression of TLR4, MyD88, and NF-kB in the hippocampus of T2DM mice. However, blocking irisin receptor signaling counteracted the down-regulation of TLR4/MyD88/NF-κB in diabetic mice undergoing exercise intervention.