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The mechanism by which Ablation of Bmal1 induces metabolic syndrome

Bmal1消融诱发代谢综合征的机制

基本信息

批准号：
20590071
负责人：
SHIMBA Shigeki
金额：
$ 3万
依托单位：
Nihon University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2010
项目状态：
已结题

项目摘要

A link between circadian rhythm and metabolism has long been discussed. Circadian rhythm is regulated by transcription factors, namely the brain and muscle Arnt-like protein-1 (BMAL1) and CLOCK. In addition to control of circadian rhythm, we have previously shown that BMAL1 regulates adipogenesis. In metabolic syndrome patients, the function of BMAL1 is dysregulated in visceral adipose tissue. Furthermore, SNPs analysis has revealed that BMAL1 is associated with susceptibility to hypertension and type II diabetes. Furthermore, the significant roles of BMAL1 in pancreatic b cells proliferation and maturation were recently reported. These results suggest that BMAL1 regulates energy homeostasis. Therefore, in this study, we examined whether loss of BMAL1 function is capable of inducing metabolic syndrome. Ablation of the Bmal1 gene in mice resulted in elevation of the respiratory quotient value, indicating that BMAL1 is involved in the utilization of fat as an energy source. Indeed, lack of Bmal1 reduced the capacity of fat storage in adipose tissue, resulting in increase the levels of circulating fatty acids, including triglycerides, free fatty acids, and cholesterol. Elevation of the circulating fatty acids level induced the formation of ectopic fat in the liver and skeletal muscle in Bmal1-/-mice. Therefore, we were led to conclude that BMAL1 is a crucial factor in the regulation of energy homeostasis, and disorders of the molecular clock system lead to development of the metabolic syndrome.

昼夜节律和新陈代谢之间的联系已经讨论了很久。昼夜节律受转录因子调节，即脑和肌肉Arnt样蛋白-1（BMAL 1）和CLOCK。除了控制昼夜节律，我们以前已经表明，BMAL 1调节脂肪形成。在代谢综合征患者中，内脏脂肪组织中BMAL 1的功能失调。此外，SNPs分析显示BMAL 1与高血压和II型糖尿病的易感性相关。此外，最近报道了BMAL 1在胰腺B细胞增殖和成熟中的重要作用。这些结果表明，BMAL 1调节能量稳态。因此，在这项研究中，我们研究了BMAL 1功能的丧失是否能够诱导代谢综合征。在小鼠中切除Bmal 1基因导致呼吸商值升高，表明BMAL 1参与了脂肪作为能量来源的利用。事实上，缺乏Bmal 1降低了脂肪组织中脂肪储存的能力，导致循环脂肪酸水平增加，包括甘油三酯，游离脂肪酸和胆固醇。循环脂肪酸水平的升高诱导了Bmal 1-/-小鼠肝脏和骨骼肌中异位脂肪的形成。因此，我们得出结论，BMAL 1是调节能量稳态的关键因素，分子钟系统的紊乱导致代谢综合征的发展。