IKKβ/NF-κB disrupts adult hypothalamic neural stem cells to mediate a neurodegenerative mechanism of dietary obesity and pre-diabetes

Adult neural stem cells (NSCs) are known to exist in a few regions of the brain; however, the entity and physiological/disease relevance of adult hypothalamic NSCs (htNSCs) remain unclear. This work shows that adult htNSCs are multipotent and predominantly present in the mediobasal hypothalamus of adult mice. Chronic high-fat-diet feeding led to not only depletion but also neurogenic impairment of htNSCs associated with IKK beta/NF-kappa B activation. In vitro htNSC models demonstrated that their survival and neurogenesis markedly decreased on IKK beta/NF-kappa B activation but increased on IKK beta/NF-kappa B inhibition, mechanistically mediated by IKK beta/NF-kappa B-controlled apoptosis and Notch signalling. Mouse studies revealed that htNSC-specific IKK beta/NF-kappa B activation led to depletion and impaired neuronal differentiation of htNSCs, and ultimately the development of obesity and pre-diabetes. In conclusion, adult htNSCs are important for the central regulation of metabolic physiology, and IKK beta/NF-kappa B-mediated impairment of adult htNSCs is a critical neurodegenerative mechanism for obesity and related diabetes.