Abstract
Ghrelin has recently been associated with the development of diabetes comorbid with depression, but its underlying molecular mechanisms remains poorly understood. Here, molecular and histological methods were applied both in vivo and in vitro studies to investigate the mechanisms of ghrelin in diabetes comorbid with depression. Our results demonstrated the anti-depressive, anxiolytic, and neuroprotective effects of ghrelin, as evidenced by the amelioration of anxiety- and depression-like behaviors, reduction in apoptosis, and preservation of neuron integrity in streptozotocin (STZ)-treated rats. STZ treatment induced M1-phenotypic microglial polarization, accompanied by neuroinflammation, which was reversed by ghrelin treatment. Further exploration showed that autophagy was inhibited, the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and nuclear factor (NF)-κB signaling pathway were activated in STZ rats. In line with the in vivo results, ghrelin could suppress the NLRP3 inflammasome and NF-κB signaling pathway activation via the amelioration of impaired autophagic flux in microglial BV2 cells. Importantly, clinical evidence further verified the anti-inflammatory and antidepressant effects of ghrelin. Collectively, these results suggested that ghrelin ameliorates diabetes-associated behavioral deficits and NLRP3 inflammasome activation via autophagic flux enhancement, highlighting the importance of ghrelin as a potential target of immune regulation in diabetes comorbid with depression.