title: CLOCK is involved in obesity-induced disordered fibrinolysis in ob/ob mice by regulating PAI-1 gene expression.
abstract: BACKGROUND
  An increased level of obesity-induced plasma plasminogen activator inhibitor-1 (PAI-1) is considered a risk factor for cardiovascular disease.
  
  
  OBJECTIVE
  The present study investigates whether the circadian clock component CLOCK is involved in obesity-induced PAI-1 elevation.
  
  
  METHODS
  We examined plasma PAI-1 and mRNA expression levels in tissues from leptin-deficient obese and diabetic ob/ob mice lacking functional CLOCK protein.
  
  
  RESULTS
  Our results demonstrated that plasma PAI-1 levels were augmented in a circadian manner in accordance with the mRNA expression levels in ob/ob mice. Surprisingly, a Clock mutation normalized the plasma PAI-1 concentrations in accordance with the mRNA levels in the heart, lung and liver of ob/ob mice, but significantly increased PAI-1 mRNA levels in adipose tissue by inducing adipocyte hypertrophy in ob/ob mice. The Clock mutation also normalized tissue PAI-1 antigen levels in the liver but not in the adipose tissue of ob/ob mice.
  
  
  CONCLUSIONS
  These observations suggest that CLOCK is involved in obesity-induced disordered fibrinolysis by regulating PAI-1 gene expression in a tissue-dependent manner. Furthermore, it appears that obesity-induced PAI-1 production in adipose tissue is not closely related to systemic PAI-1 increases in vivo.
authors.affiliation: Clock Cell Biology Research Group, Institute for Biological Resources and Functions, National Institute of Advanced Industrial Science and Technology, Higashi, Tsukuba, Ibaraki, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Oishi
authors.forename: N
authors.initials: N
authors.lastname: Ohkura
authors.forename: M
authors.initials: M
authors.lastname: Wakabayashi
authors.forename: H
authors.initials: H
authors.lastname: Shirai
authors.forename: K
authors.initials: K
authors.lastname: Sato
authors.forename: J
authors.initials: J
authors.lastname: Matsuda
authors.forename: G
authors.initials: G
authors.lastname: Atsumi
authors.forename: N
authors.initials: N
authors.lastname: Ishida
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D056926:CLOCK Proteins; D002940:Circadian Rhythm; D005342:Fibrinolysis; D005786:Gene Expression Regulation; D006579:Heterozygote; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008820:Mice, Obese; D009765:Obesity / Q000235:genetics*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D015534:Trans-Activators; D056926:CLOCK Proteins; C538944:Clock protein, mouse