Bmal1 is required for beta cell compensatory expansion, survival and metabolic adaptation to diet-induced obesity in mice.
Bmal1 is required for beta cell compensatory expansion, survival and metabolic adaptation to diet-induced obesity in mice.
复制标题
DOI：
10.1007/s00125-015-3859-2
复制
发表时间：
2016-04
期刊：
影响因子：
8.2
通讯作者：
Matveyenko AV
中科院分区：
文献类型：
--
作者：
Rakshit K;Hsu TW;Matveyenko AV
肥胖和随之而来的胰岛素抵抗是2型糖尿病的已知危险因素。响应于胰岛素抵抗的β细胞功能和质量的代偿性增加允许维持正常的葡萄糖稳态，而不能这样做会导致β细胞衰竭和2型糖尿病。最近的证据表明，昼夜节律系统对于适当的代谢控制和β细胞功能的调节是必不可少的。我们着手解决的假设，β细胞生物钟是必不可少的适当的功能和形态β细胞胰岛素抵抗的反应。我们使用他莫昔芬诱导的CreERT重组系统在β细胞中采用了Bmal1（也称为Arntl）基因（编码关键的昼夜节律钟转录因子）的条件性缺失。在成年后，实现β细胞中的Bmal1缺失，并将小鼠暴露于食物或高脂肪饮食（HFD）。昼夜血糖，葡萄糖耐量和胰岛素分泌的变化进行了纵向监测体内和胰岛形态和周转免疫荧光评估。进行体外分离的胰岛实验以描绘β细胞功能和细胞增殖的转录调节的变化。β细胞中的成人Bmal1缺失导致对HFD的代谢适应失败，其特征为空腹和昼夜高血糖症、葡萄糖耐受不良和葡萄糖刺激的胰岛素分泌丧失。重要的是，在β细胞Bmal1缺失后不存在HFD诱导的β细胞扩增，表明β细胞增殖和再生潜力受损，这通过评估分离的胰岛中的转录谱得到证实。研究结果表明，β细胞昼夜节律钟是一种新型的调节剂，可调节β细胞的代偿性扩张和功能，以响应与饮食诱导的肥胖相关的胰岛素需求增加。
Obesity and consequent insulin resistance are known risk factors for type 2 diabetes. A compensatory increase in beta cell function and mass in response to insulin resistance permits maintenance of normal glucose homeostasis, whereas failure to do so results in beta cell failure and type 2 diabetes. Recent evidence suggests that the circadian system is essential for proper metabolic control and regulation of beta cell function. We set out to address the hypothesis that the beta cell circadian clock is essential for the appropriate functional and morphological beta cell response to insulin resistance. We employed conditional deletion of the Bmal1 (also known as Arntl) gene (encoding a key circadian clock transcription factor) in beta cells using the tamoxifen-inducible CreERT recombination system. Upon adulthood, Bmal1 deletion in beta cells was achieved and mice were exposed to either chow or high fat diet (HFD). Changes in diurnal glycaemia, glucose tolerance and insulin secretion were longitudinally monitored in vivo and islet morphology and turnover assessed by immunofluorescence. Isolated islet experiments in vitro were performed to delineate changes in beta cell function and transcriptional regulation of cell proliferation. Adult Bmal1 deletion in beta cells resulted in failed metabolic adaptation to HFD characterised by fasting and diurnal hyperglycaemia, glucose intolerance and loss of glucose-stimulated insulin secretion. Importantly, HFD-induced beta cell expansion was absent following beta cell Bmal1 deletion indicating impaired beta cell proliferative and regenerative potential, which was confirmed by assessment of transcriptional profiles in isolated islets. Results of the study suggest that the beta cell circadian clock is a novel regulator of compensatory beta cell expansion and function in response to increased insulin demand associated with diet-induced obesity.