Dual attenuation of proteasomal and autophagic BMAL1 degradation in Clock Δ19/+ mice contributes to improved glucose homeostasis.
Dual attenuation of proteasomal and autophagic BMAL1 degradation in Clock Δ19/+ mice contributes to improved glucose homeostasis.
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DOI：
10.1038/srep12801
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发表时间：
2015-07-31
影响因子：
4.6
通讯作者：
Chen Z
中科院分区：
文献类型：
--
作者：
Jeong K;He B;Nohara K;Park N;Shin Y;Kim S;Shimomura K;Koike N;Yoo SH;Chen Z
生物钟协调基本的生理反应的各种线索，但其机制和功能的可塑性仍然不清楚。在这里，我们研究了ClockΔ19/+杂合子（Clk/+）小鼠，已知其显示出延长的周期性和阻尼的振幅，作为部分扰动时钟的模型。有趣的是，Clk/+小鼠在高脂饮食（HFD）下表现出改善的血糖控制和对昼夜节律周期延长的抗性。此外，与HFD下的野生型（WT）小鼠相比，Clk/+小鼠肝脏中的BMAL 1蛋白水平上调。药理学和分子研究表明，BMAL 1周转需要蛋白酶体和自噬活性，而CLOCKΔ19减弱了这两个过程。与BMAL 1在血糖控制中的重要作用一致，在HFD中，相对于WT，在Clk/+小鼠中观察到胰岛素信号传导的增强激活。最后，转录组分析揭示了Clk/+小鼠中时钟控制的代谢基因的重编程。我们的研究结果证明了自噬在昼夜节律调节中的新作用，并揭示了昼夜节律和代谢网络的不可预见的可塑性。
Circadian clocks orchestrate essential physiology in response to various cues, yet their mechanistic and functional plasticity remains unclear. Here, we investigated ClockΔ19/+ heterozygous (Clk/+) mice, known to display lengthened periodicity and dampened amplitude, as a model of partially perturbed clocks. Interestingly, Clk/+ mice exhibited improved glycemic control and resistance to circadian period lengthening under high-fat diet (HFD). Furthermore, BMAL1 protein levels in Clk/+ mouse liver were upregulated compared with wild-type (WT) mice under HFD. Pharmacological and molecular studies showed that BMAL1 turnover entailed proteasomal and autophagic activities, and CLOCKΔ19 attenuated both processes. Consistent with an important role of BMAL1 in glycemic control, enhanced activation of insulin signaling was observed in Clk/+ mice relative to WT in HFD. Finally, transcriptome analysis revealed reprogramming of clock-controlled metabolic genes in Clk/+ mice. Our results demonstrate a novel role of autophagy in circadian regulation and reveal an unforeseen plasticity of circadian and metabolic networks.