IKKβ/NF-κB Disrupts Adult Hypothalamic Neural Stem Cells to Mediate Neurodegenerative Mechanism of Dietary Obesity and Pre-Diabetes

Adult neural stem cells (NSCs) are known to exist in a few brain regions; however, the entity and physiological/disease relevance of adult hypothalamic NSCs (htNSCs) remain unclear. Here, this work showed that adult htNSCs are multipotent and predominantly present in the mediobasal hypothalamus of adult-aged mice. Chronic high-fat-diet feeding led to not only depletion but also neurogenic impairment of htNSCs associated with IKKβ/NF-κB activation. In vitro htNSC models demonstrated that their survival and neurogenesis dramatically decreased upon IKKβ/NF-κB activation but increased upon IKKβ/NF-κB inhibition, mechanistically mediated by IKKβ/NF-κB-controlled apoptosis and Notch signaling. Mouse studies revealed that htNSC-specific IKKβ/NF-κB 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 central regulation of metabolic physiology, and IKKβ/NF-κB-mediated impairment of adult htNSCs is a critical neurodegenerative mechanism for obesity and related diabetes.