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

Nature Cell Biology volume 14, pages 999–1012 (2012)Cite this article

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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.

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Figure 1: In vivo and in vitro definition of htNSCs in adult mice.
Figure 2: BrdU tracking of adult htNSCs-mediated neurogenesis in mice.
Figure 3: Fate mapping of adult htNSCs in mice under normal physiological conditions.
Figure 4: Impaired survival and neurogenesis of htNSCs derived from mice with dietary obesity.
Figure 5: Impaired in vitro proliferation of htNSCs with IKKβ/NF-κB activation.
Figure 6: In vitro effect of IKKβ/NF-κB activation on neuronal differentiation of htNSCs.
Figure 7: Effect of NF- κB inhibition on the differentiation of htNSCs derived from obese mice.
Figure 8: Mouse model of htNSCs-specific IKKβ activation and metabolic phenotypes.

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Acknowledgements

The authors sincerely thank F. H. Gage (The Salk Institute for Biological Studies, USA) for the Sox2-promoter-containing lentiviral vector, D. Hickstein (National Cancer Institute, National Institutes of Health, USA) for the CD11b-promoter cDNA, and the members of the Cai laboratory for general technical assistance. This study was supported by Albert Einstein College of Medicine internal start-up funds and NIH R01 DK078750 and R01 AG031774 (all to D. Cai).

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Authors and Affiliations

  1. Department of Molecular Pharmacology, Bronx, New York 10461, USA

    Juxue Li, Yizhe Tang & Dongsheng Cai

  2. Diabetes Research and Training Center, Bronx, New York 10461, USA

    Juxue Li, Yizhe Tang & Dongsheng Cai

  3. Institute of Aging, Albert Einstein College of Medicine, Bronx, New York 10461, USA

    Juxue Li, Yizhe Tang & Dongsheng Cai

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  1. Juxue Li
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Contributions

D.C. conceived the project and designed the study. J.L. carried out all experiments and participated in the experimental design. Y.T. generated luciferase constructs of wild-type and mutant Notch signalling element gene promoters. J.L. and D.C. carried out data interpretation and discussion. D.C. wrote the paper.

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Correspondence to Dongsheng Cai.

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The authors declare no competing financial interests.

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Li, J., Tang, Y. & Cai, D. IKKβ/NF-κB disrupts adult hypothalamic neural stem cells to mediate a neurodegenerative mechanism of dietary obesity and pre-diabetes. Nat Cell Biol 14, 999–1012 (2012). https://doi.org/10.1038/ncb2562

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