Extreme obesity induces massive beta cell expansion in mice through self-renewal and does not alter the beta cell lineage.
Extreme obesity induces massive beta cell expansion in mice through self-renewal and does not alter the beta cell lineage.
复制标题
DOI：
10.1007/s00125-016-3922-7
复制
发表时间：
2016-06
期刊：
影响因子：
8.2
通讯作者：
Kushner JA
中科院分区：
文献类型：
--
作者：
Cox AR;Lam CJ;Rankin MM;King KA;Chen P;Martinez R;Li C;Kushner JA
了解 β 细胞再生的发育生物学对于开发新的糖尿病疗法至关重要。肥胖是β细胞扩张的一种有效刺激因素，但人们对此知之甚少。目前的肥胖模型因发育补偿或并发糖尿病而变得复杂，限制了它们在识别β细胞扩增谱系机制方面的有用性。我们的目的是确定急性诱导性肥胖是否会刺激 β 细胞扩增，并确定肥胖中 β 细胞生长的谱系机制。我们创建了全身他莫昔芬诱导瘦素受体 (LepR) 缺陷的小鼠 (Ubc-CreERT2LepRloxP/loxP) 作为急性肥胖的新型模型。短期 LepR 缺失后对 β 细胞质量和增殖进行了定量。在他莫昔芬开始治疗 6 个月后，使用 Brainbow2.1 报告基因对 β 细胞扩增进行克隆分析。 LepR 缺陷导致体重在 3 周内翻倍，并伴有中度葡萄糖不耐受（与典型的 LepR 突变小鼠 [db/db] 不同，后者患有明显的糖尿病）。通过增加 β 细胞增殖，β 细胞质量扩大了三倍，而没有证据表明来自专门祖细胞或干细胞的贡献（通过连续胸苷标记和 Brainbow2.1 报告基因）。因此，自我更新是肥胖诱导的 β 细胞扩增的主要谱系机制。然而，即使快速增殖的β细胞也无法超过复制不应期的限制。总之，我们创建了一种新的诱导性肥胖模型，证明即使是极端的代谢需求也不会改变 β 细胞谱系。本文的在线版本 (doi:10.1007/s00125-016-3922-7) 包含经过同行评审但未经编辑的补充材料，可供授权用户使用。
Understanding the developmental biology of beta cell regeneration is critical for developing new diabetes therapies. Obesity is a potent but poorly understood stimulus for beta cell expansion. Current models of obesity are complicated by developmental compensation or concurrent diabetes, limiting their usefulness for identifying the lineage mechanism(s) of beta cell expansion. We aimed to determine whether acute inducible obesity stimulates beta cell expansion and to determine the lineage mechanism of beta cell growth in obesity. We created whole-body tamoxifen-inducible leptin receptor (LepR)-deficient mice (Ubc-CreERT2LepRloxP/loxP) as a novel model of acute obesity. Beta cell mass and proliferation were quantified after short-term LepR deletion. Clonal analysis of beta cell expansion using the Brainbow2.1 reporter was performed 6 months post tamoxifen initiation. LepR deficiency induced a doubling of body mass within 3 weeks, with moderate glucose intolerance (unlike typical LepR mutant mice [db/db], which have frank diabetes). Beta cell mass expanded threefold through increased beta cell proliferation, without evidence for contribution from specialised progenitors or stem cells (via sequential thymidine labelling and Brainbow2.1 reporter). Thus, self-renewal is the primary lineage mechanism in obesity-induced beta cell expansion. However, even the rapid beta cell proliferation could not exceed the restrictions of the replication refractory period. In summary, we created a novel model of inducible obesity demonstrating that even extreme metabolic demand does not alter beta cell lineage. The online version of this article (doi:10.1007/s00125-016-3922-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.