Notch signaling dynamically regulates adult β cell proliferation and maturity
Notch signaling dynamically regulates adult β cell proliferation and maturity
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DOI：
10.1172/jci98098
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发表时间：
2019-01-02
影响因子：
15.9
通讯作者：
Pajvani, Utpal B.
中科院分区：
文献类型：
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作者：
Bartolome, Alberto;Zhu, Changyu;Pajvani, Utpal B.
Notch信号在胚胎发生过程中调节胰腺内分泌谱系的分化，但Notch在成熟β细胞中的作用尚不清楚。我们发现来自瘦老鼠的胰岛显示出适度的β细胞Notch活性，这种活性在肥胖和高葡萄糖反应中增加。这种反应似乎是不适应的，因为β细胞特异性Notch转录活性缺乏的小鼠在接受高脂肪饮食喂养时表现出改善的葡萄糖耐量。相反，具有β细胞特异性Notch功能获得（β - nico）的小鼠由于蛋白酶体降解MafA而逐渐丧失β细胞成熟度，导致葡萄糖刺激的胰岛素分泌受损，并随着衰老或肥胖而出现葡萄糖耐受不良。令人惊讶的是，notch活性β细胞的增殖能力增加，导致β细胞质量增加但功能失调。这些研究表明Notch在发育的β细胞中具有动态作用，可以同时调节β细胞的功能和增殖。
Notch signaling regulates differentiation of the pancreatic endocrine lineage during embryogenesis, but the role of Notch in mature beta cells is unclear. We found that islets derived from lean mice show modest beta cell Notch activity, which increases in obesity and in response to high glucose. This response appeared maladaptive, as mice with beta cell-specific-deficient Notch transcriptional activity showed improved glucose tolerance when subjected to high-fat diet feeding. Conversely, mice with beta cell-specific Notch gain of function (beta-NICO) had a progressive loss of beta cell maturity, due to proteasomal degradation of MafA, leading to impaired glucose-stimulated insulin secretion and glucose intolerance with aging or obesity. Surprisingly, Notch-active beta cells had increased proliferative capacity, leading to increased but dysfunctional beta cell mass. These studies demonstrate a dynamic role for Notch in developed beta cells for simultaneously regulating beta cell function and proliferation.