title: Dual attenuation of proteasomal and autophagic BMAL1 degradation in Clock Δ19/+ mice contributes to improved glucose homeostasis.
abstract: Circadian clocks orchestrate essential physiology in response to various cues, yet their mechanistic and functional plasticity remains unclear. Here, we investigated Clock(Δ19/+) 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030.
authors.forename: Kwon
authors.initials: K
authors.lastname: Jeong
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030.
authors.forename: Baokun
authors.initials: B
authors.lastname: He
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Nohara
authors.affiliation: Department of Neuroscience, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390.
authors.forename: Noheon
authors.initials: N
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030.
authors.forename: Youngmin
authors.initials: Y
authors.lastname: Shin
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030.
authors.forename: Seonghwa
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Neurobiology and Physiology, Center for Sleep and Circadian Biology, Northwestern University, 2205 Tech Drive, Evanston, IL 60201.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shimomura
authors.affiliation: Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Koike
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030.
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Yoo
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
mesh_terms: D056930:ARNTL Transcription Factors / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D001786:Blood Glucose / Q000378:metabolism*; D056926:CLOCK Proteins / Q000235:genetics* / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology; D059305:Diet, High-Fat / Q000009:adverse effects; D005786:Gene Expression Regulation; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008817:Mice, Mutant Strains; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D000071456:Sequestosome-1 Protein / Q000378:metabolism
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D001786:Blood Glucose; D007328:Insulin; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D056926:CLOCK Proteins; C538944:Clock protein, mouse; D046988:Proteasome Endopeptidase Complex