title: Deficient of a clock gene, brain and muscle Arnt-like protein-1 (BMAL1), induces dyslipidemia and ectopic fat formation.
abstract: A link between circadian rhythm and metabolism has long been discussed. Circadian rhythm is controlled by positive and negative transcriptional and translational feedback loops composed of several clock genes. Among clock genes, the brain and muscle Arnt-like protein-1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK) play important roles in the regulation of the positive rhythmic transcription. 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. In addition, analysis of SNPs has revealed that BMAL1 is associated with susceptibility to hypertension and type II diabetes. Furthermore, the significant roles of BMAL1 in pancreatic β 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. Deficient 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 an increase in 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. Interestingly, ectopic fat formation was not observed in tissue-specific (liver or skeletal muscle) Bmal1 -/- mice even under high fat diet feeding condition. Therefore, we were led to conclude that BMAL1 is a crucial factor in the regulation of energy homeostasis, and disorders of the functions of BMAL1 lead to the development of metabolic syndrome.
authors.affiliation: Department of Health Science, School of Pharmacy, Nihon University, Funabashi, Chiba, Japan. shimba.shigeki@nihon-u.ac.jp
authors.forename: Shigeki
authors.initials: S
authors.lastname: Shimba
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ogawa
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Hitosugi
authors.forename: Yuya
authors.initials: Y
authors.lastname: Ichihashi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nakadaira
authors.forename: Munehiro
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Tezuka
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kosuge
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ishige
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Ito
authors.forename: Kazuo
authors.initials: K
authors.lastname: Komiyama
authors.forename: Yuko
authors.initials: Y
authors.lastname: Okamatsu-Ogura
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kimura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Saito
mesh_terms: D056930:ARNTL Transcription Factors / Q000172:deficiency* / Q000235:genetics; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D050171:Dyslipidemias / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D005227:Fatty Acids; D014280:Triglycerides; D002784:Cholesterol