Non-canonical mitochondrial STAT3 signaling mediates exercise-induced insulin secretion down-regulation

Chronic exercise protects pancreatic beta cells from diabetogenic stress, reducing insulin secretion through unknown mechanisms. We tested the hypothesis that the IL-6/mitochondrial STAT3 (pS-STAT3) axis plays a role in this protective effect. C57BL/6N mice were subjected to endurance training ahead of pancreatic islet isolation and functional analysis. Similar in vitro experiments were performed using insulin-producing INS-1E cells and islets from untrained mice, cultured with serum from trained animals and treated with or without an IL-6 receptor (IL-6R) inhibitor. Then, IL-6R/pS-STAT3 pathway activation and its effects on mitochondrial function and insulin secretion were assessed. Exercise-induced down-regulation of insulin secretion was prevented by inhibition of IL-6R signaling and following STAT3 knockdown. IL-6R activation promoted STAT3 phosphorylation and translocation to the mitochondria, increasing oxygen consumption. Accordingly, lower H2O2 content was reported in islets from trained mice and beta cells exposed to exercise-conditioned serum, while exposure to exogenous H2O2 blocked the down-regulatory effect of training on insulin secretion. Similar findings were observed in islets from obese-trained mice. Together, these findings suggest that the IL-6R/pS-STAT3 axis mediates exercise-induced down-regulation of insulin secretion through modulation of the mitochondrial redox state.