Asprosin mediates diabetes-associated depression via provoking the cascade of pyroptosis-neuroinflammation-kynurenine pathway disorder in the hippocampus

Depression is a frequent neuropsychiatric complication of diabetes mellitus, but the underlying molecular mechanisms of diabetes-associated depression remain poorly understood. Asprosin, a recently identified fasting-induced glucogenic adipokine, is significantly elevated in diabetes. Pyroptosis, a form of inflammatory programmed cell death, can induce robust neuroinflammation, which also disrupts the kynurenine pathway (KP) of tryptophan metabolism, implying a potential cascade of pyroptosis-neuroinflammation-KP disorder relevant to depression pathogenesis. Therefore, this study aimed to elucidate whether hippocampal Asprosin contributes to the development of diabetes-associated depression by modulating this cascade. A rat model of diabetes-associated depression was established using a high-fat diet and streptozotocin (HFD/STZ). Results showed that diabetic rats exhibited increased depression-like behaviors, accompanied by elevated hippocampal Asprosin levels. Hippocampal Asprosin knockdown significantly alleviated depression-like behaviors, notably without affecting systemic glucose metabolism in diabetic rats, whereas hippocampal Asprosin overexpression induced depression-like behaviors. Mechanistically, Asprosin knockdown attenuated hippocampal neuroinflammation, suppressed astrocyte/microglial activation, and inhibited pyroptosis. Furthermore, Asprosin knockdown also restored KP homeostasis by reducing levels of neurotoxic metabolites (KYN, 3-HK, 3-HAA, QA) and increasing NAD⁺ levels in the hippocampus of diabetic rats. Conversely, Asprosin overexpression exacerbated hippocampal neuroinflammation, pyroptosis, and KP disorder. These findings suggest that hippocampal Asprosin may contribute to diabetes-associated depression, possibly by provoking the cascade of pyroptosis-neuroinflammation-KP disorder.