title: The production of coagulation factor VII by adipocytes is enhanced by tumor necrosis factor-α or isoproterenol.
abstract: BACKGROUND
  A relationship has been reported between blood concentrations of coagulation factor VII (FVII) and obesity. In addition to its role in coagulation, FVII has been shown to inhibit insulin signals in adipocytes. However, the production of FVII by adipocytes remains unclear.
  
  
  OBJECTIVE
  We herein investigated the production and secretion of FVII by adipocytes, especially in relation to obesity-related conditions including adipose inflammation and sympathetic nerve activation.
  
  
  METHODS
  C57Bl/6J mice were fed a low- or high-fat diet and the expression of FVII messenger RNA (mRNA) was then examined in adipose tissue. 3T3-L1 cells were used as an adipocyte model for in vitro experiments in which these cells were treated with tumor necrosis factor-α (TNF-α) or isoproterenol. The expression and secretion of FVII were assessed by quantitative real-time PCR, Western blotting and enzyme-linked immunosorbent assays.
  
  
  RESULTS
  The expression of FVII mRNA in the adipose tissue of mice fed with high-fat diet was significantly higher than that in mice fed with low-fat diet. Expression of the FVII gene and protein was induced during adipogenesis and maintained in mature adipocytes. The expression and secretion of FVII mRNA were increased in the culture medium of 3T3-L1 adipocytes treated with TNF-α, and these effects were blocked when these cells were exposed to inhibitors of mitogen-activated kinases or NF-κB activation. The β-adrenoceptor agonist isoproterenol stimulated the secretion of FVII from mature adipocytes via the cyclic AMP/protein kinase A pathway. Blockade of secreted FVII with the anti-FVII antibody did not affect the phosphorylation of Akt in the isoproterenol-stimulated adipocytes.
  
  
  CONCLUSIONS
  Obese adipose tissue produced FVII. The production and secretion of FVII by adipocytes was enhanced by TNF-α or isoproterenol via different mechanisms. These results indicate that FVII is an adipokine that plays an important role in the pathogenesis of obesity.
authors.affiliation: 1] Department of Internal Medicine, School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan [2] Department of Medicine, Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Department of Biotechnology, Faculty of Life Science and Biotechnology, Fukuyama University, Fukuyama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yoshizaki
authors.affiliation: Department of Internal Medicine, School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Hiranaka
authors.affiliation: 1] Department of Internal Medicine, School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan [2] Hemostasis Product Engineering, Sysmex Corporation, Kobe, Japan.
authors.forename: O
authors.initials: O
authors.lastname: Kumano
authors.affiliation: 1] Department of Internal Medicine, School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan [2] Hemostasis Product Engineering, Sysmex Corporation, Kobe, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Fixed Prosthodontics and Oral Implantology, School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Akanuma
authors.affiliation: Department of Fixed Prosthodontics and Oral Implantology, School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yui
authors.affiliation: Department of Dental Anesthesiology, School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kanazawa
authors.affiliation: Department of Clinical Laboratory, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Department of Clinical Laboratory, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Naito
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Fujiya
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kohgo
authors.affiliation: Department of Internal Medicine, School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ieko
mesh_terms: D041721:3T3-L1 Cells / Q000378:metabolism*; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D018752:Diet, Fat-Restricted; D059305:Diet, High-Fat; D005167:Factor VII / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D007545:Isoproterenol / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000318:Adrenergic beta-Agonists; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D005167:Factor VII; D007545:Isoproterenol