Department of Molecular Pharmacology, Bronx, New York 10461, USA.
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.
成年神经干细胞（NSCs）已知存在于大脑的几个区域；然而，成年下丘脑 NSCs（htNSCs）的实体和生理/疾病相关性仍不清楚。这项工作表明，成年 htNSCs 具有多能性，主要存在于成年小鼠的中脑基底部下丘脑。慢性高脂肪饮食喂养不仅导致 htNSCs 的耗竭，而且与 IKKβ/NF-κB 激活相关的神经发生受损。体外 htNSC 模型表明，它们的存活和神经发生在 IKKβ/NF-κB 激活时显著减少，而在 IKKβ/NF-κB 抑制时增加，这是由 IKKβ/NF-κB 控制的细胞凋亡和 Notch 信号传导介导的。小鼠研究表明，htNSC 特异性 IKKβ/NF-κB 激活导致 htNSCs 的耗竭和神经元分化受损，最终导致肥胖和前驱糖尿病的发生。总之，成年 htNSCs 对代谢生理学的中枢调节很重要，而 IKKβ/NF-κB 介导的成年 htNSCs 损伤是肥胖和相关糖尿病的关键神经退行性机制。
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