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

Nat Cell Biol. 2012 Oct;14(10):999-1012. doi: 10.1038/ncb2562. Epub 2012 Sep 2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Diet, High-Fat / adverse effects*
  • Hypothalamus / physiopathology*
  • I-kappa B Kinase / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / physiology*
  • Neural Stem Cells / physiology*
  • Neurodegenerative Diseases / physiopathology*
  • Obesity / physiopathology*
  • Prediabetic State / physiopathology
  • Receptors, Notch / physiology
  • Signal Transduction / physiology


  • NF-kappa B
  • Receptors, Notch
  • I-kappa B Kinase