Dual attenuation of proteasomal and autophagic BMAL1 degradation in Clock δ "19/+ mice contributes to improved glucose homeostasis

Kwon Jeong, Baokun He, Kazunari Nohara, Noheon Park, Youngmin Shin, Seonghwa Kim, Kazuhiro Shimomura, Nobuya Koike, Seung Hee Yoo, Zheng Chen

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Circadian clocks orchestrate essential physiology in response to various cues, yet their mechanistic and functional plasticity remains unclear. Here, we investigated Clock δ"19/+ 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 CLOCKδ"19 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.

Original languageEnglish (US)
Article number12801
JournalScientific Reports
Publication statusPublished - Jul 31 2015


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