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Troxerutin attenuates insulin resistance via pancreatic IL-22/JAK1/STAT3 signaling activation in dihydrotestosterone-induced PCOS rats.

Polycystic ovary syndrome (PCOS) is an extremely common endocrine-metabolic disorder and the main cause of infertility in premenopausal women, thus targeted treatments are sorely needed. Accumulative evidence showed that exogenous supplementation of IL-22 in PCOS mice may be of significantly positive effect on insulin resistance, a root causative factor for this condition, but much remained unknown about its mechanism. According to our previous study, troxerutin, a common anticoagulant and thrombolytic agent in clinic, alleviated various PCOS-like phenotypes in dihydrotestosterone (DHT)-treated rat model with unclear mechanism. Here, GTTs, ITTs and HOMA-IR analyses revealed that troxerutin treatment to DHT-treated rats also significantly improved insulin resistance and enhanced serum IL-22 levels, which thereby activated IL-22R1/JAK1/STAT3 signaling pathway in pancreatic islet. This protective effect of troxerutin on insulin resistance improvement was blocked by an inhibitor of p-STAT3, S3I-201. Troxerutin administration to DHT rats decreased the relative abundance of Bifidobacterium and enhanced secondary bile acid profiles, which were positively correlated with serum IL-22 concentration. Conclusively, the present study reported that troxerutin is an endogenous enhancer of IL-22 and the effect of troxerutin on insulin resistance improvement was via IL-22R1/JAK1/STAT3 signaling activation in a DHT-induced PCOS rat model. These insights may be translated into a primary therapeutic agent for PCOS with insulin resistance and hyperandrogenism.