The mechanism by which Ablation of Bmal1 induces metabolic syndrome

昼夜节律和新陈代谢之间的联系早已被讨论过。昼夜节律是由转录因子调节的，即脑和肌肉的art -like protein-1 （BMAL1）和CLOCK。除了控制昼夜节律，我们之前已经证明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分析显示BMAL1与高血压和II型糖尿病的易感性相关。此外，最近报道了BMAL1在胰腺b细胞增殖和成熟中的重要作用。这些结果表明BMAL1调节能量稳态。因此，在本研究中，我们研究了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Bmal1参与了脂肪作为能量来源的利用。事实上，缺乏Bmal1会降低脂肪组织中的脂肪储存能力，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。循环脂肪酸水平升高诱导Bmal1-/-小鼠肝脏和骨骼肌异位脂肪的形成。因此，我们得出结论，BMAL1是调节能量稳态的关键因素，分子时钟系统的紊乱导致代谢综合征的发生。

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.