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.

长期以来讨论了昼夜节律与代谢之间的联系。昼夜节律受转录因子的调节，即大脑和肌肉类似蛋白-1（BMAL1）和时钟。除了控制昼夜节律外，我们先前表明BMAL1调节脂肪形成。在代谢综合征患者中，内脏脂肪组织中BMAL1的功能失调。此外，SNP分析表明，BMAL1与高血压和II型糖尿病的敏感性有关。此外，最近报道了BMAL1在胰腺B细胞增殖和成熟中的显着作用。这些结果表明BMAL1调节能量稳态。因此，在这项研究中，我们检查了BMAL1功能的丧失是否能够诱导代谢综合征。小鼠BMAL1基因的消融导致呼吸商值升高，表明BMAL1参与了将脂肪作为能源的利用。实际上，缺乏BMAL1会降低脂肪组织中脂肪储存的能力，从而增加循环脂肪酸的水平，包括甘油三酸酯，游离脂肪酸和胆固醇。循环脂肪酸水平的升高诱导肝脏中异位脂肪的形成和BMAL1 - / - 小鼠中的骨骼肌。因此，我们得出的结论是，BMAL1是能量稳态调节的关键因素，并且分子时钟系统的疾病导致了代谢综合征的发展。