A Potential Link Between Early Onset Reactive Astrogliosis and Adult-Onset Dysfunction of Leptin Signaling in Polyubiquitin Gene Ubb Knockout Mice.

BACKGROUND

Polyubiquitin gene Ubb knockout (KO) mice exhibit early onset reactive astrogliosis and adult-onset hypothalamic neurodegeneration with obesity. However, it remains unknown why the obesity phenotype only manifests in adulthood and why mice are smaller at an early age. Therefore, this study aimed to identify the link between neuroinflammation at an early age and adult-onset leptin signaling dysfunction in Ubb KO mice.

METHODS

To investigate neuroinflammatory marker expression in the hypothalamus of Ubb KO mice, RNA-seq analysis and quantitative reverse transcription-polymerase chain reaction were used. Moreover, astrocytes isolated from postnatal brains were cultured and pure astrocytes were obtained by magnetic-activated cell sorting. Furthermore, mice were challenged with lipopolysaccharide (LPS) to induce upregulation of neuroinflammatory markers, including lipocalin-2 (LCN2). Leptin signaling was examined through the administration of leptin via intraperitoneal or intracerebroventricular injection, followed by monitoring of relevant proteins using immunofluorescence and western blot analyses.

RESULTS

In Ubb KO mice, reactive astrogliosis occurred at an early age and increased the expression of Lcn2 and other neuroinflammatory markers. Upon exposure to LPS, these levels showed upward trends; however, they were comparable with those in wild-type mice, suggesting that Ubb KO mice were under intrinsic inflammatory stress. In adulthood, leptin signaling dysfunction was observed owing to elevated levels of negative regulators, such as suppressor of cytokine signaling-3 (SOCS3) and forkhead box protein O1 (FOXO1), possibly as a result of chronic neuroinflammation.

CONCLUSION

This study demonstrates that Lcn2 expression is increased in young Ubb KO mice. Although leptin signaling is intact at an early age, high LCN2 levels may contribute to reduced daily food intake and lower body weight. Chronic neuroinflammation resulting from reactive astrogliosis persists into adulthood, leading to leptin signaling dysfunction. This is most likely a result of elevated levels of SOCS3 and FOXO1, both of which are negative regulators of leptin signaling.