title: HMGB1 is secreted by 3T3-L1 adipocytes through JNK signaling and the secretion is partially inhibited by adiponectin.
abstract: Obesity is a chronic inflammatory disease, and adipocytes contribute to obesity-associated inflammation by releasing inflammatory mediators. High mobility group box 1 (HMGB1), a highly conserved DNA-binding protein, mainly localized to cell nuclei, has been recently recognized as an innate pro-inflammatory mediator when released extracellularly. It was hypothesized that HMGB1 is an adipocytokine that acts as an innate pro-inflammatory mediator in white adipose tissue (WAT) of patients with obesity and is associated with insulin resistance. Additionally, it was hypothesized that HMGB1 secretion is regulated by adiponectin.
  
  
  
  3T3-L1 cells were differentiated into mature adipocytes. After tumor necrosis factor-α (TNF-α) stimulation, HMGB1 in culture media was measured. Localizations of HMGB1 in 3T3-L1 adipocytes and human WAT were examined by immunostaining.
  
  
  
  HMGB1 was secreted from TNF-α-induced 3T3-L1 adipocytes through JNK signaling. HMGB1-activated MAP kinases (ERK1/2, JNK) and suppressed insulin-stimulated Akt phosphorylation in 3T3-L1 adipocytes. The cytoplasm in 3T3-L1 adipocytes and adipocytes of WAT from a patient with obesity was intensely stained with HMGB1. Adiponectin partially inhibited TNF-α-induced HMGB1 secretion from 3T3-L1 adipocytes.
  
  
  
  These findings suggest that HMGB1 is a pro-inflammatory adipocytokine involved in WAT inflammation and insulin resistance in patients with obesity, which may contribute to the progression of metabolic syndrome, and that adiponectin protects against HMGB1-induced adipose tissue inflammation.
authors.affiliation: Department of Laboratory and Vascular Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Laboratory and Vascular Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Munekazu
authors.initials: M
authors.lastname: Yamakuchi
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh.
authors.forename: Kamal Krishna
authors.initials: KK
authors.lastname: Biswas
authors.affiliation: Cardiovascular and Gastroenterological Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Bibek
authors.initials: B
authors.lastname: Aryal
authors.affiliation: Shino-Test Corporation, Sagamihara, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Department of Laboratory and Vascular Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Teruto
authors.initials: T
authors.lastname: Hashiguchi
authors.affiliation: Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Ikuro
authors.initials: I
authors.lastname: Maruyama
mesh_terms: D041721:3T3-L1 Cells / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism; D054392:Adipokines / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D009765:Obesity / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C499918:ADIPOQ protein, human; D054392:Adipokines; D052242:Adiponectin; D024243:HMGB1 Protein; D007328:Insulin; D014409:Tumor Necrosis Factor-alpha