title: IKKβ/NF-κB disrupts adult hypothalamic neural stem cells to mediate a neurodegenerative mechanism of dietary obesity and pre-diabetes.
abstract: 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 IKKβ/NF-κB activation. In vitro htNSC models demonstrated that their survival and neurogenesis markedly decreased on IKKβ/NF-κB activation but increased on IKKβ/NF-κB inhibition, mechanistically mediated by IKKβ/NF-κB-controlled apoptosis and Notch signalling. 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 the central regulation of metabolic physiology, and IKKβ/NF-κB-mediated impairment of adult htNSCs is a critical neurodegenerative mechanism for obesity and related diabetes.
authors.affiliation: Department of Molecular Pharmacology, Bronx, New York 10461, USA.
authors.forename: Juxue
authors.initials: J
authors.lastname: Li
authors.forename: Yizhe
authors.initials: Y
authors.lastname: Tang
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Cai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D059305:Diet, High-Fat / Q000009:adverse effects*; D007031:Hypothalamus / Q000503:physiopathology*; D051550:I-kappa B Kinase / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology*; D058953:Neural Stem Cells / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000503:physiopathology*; D009765:Obesity / Q000503:physiopathology*; D011236:Prediabetic State / Q000503:physiopathology; D051880:Receptors, Notch / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016328:NF-kappa B; D051880:Receptors, Notch; D051550:I-kappa B Kinase