title: Immunological blockade of adipocyte inflammation caused by increased matrix metalloproteinase-cleaved osteopontin in obesity.
abstract: OBJECTIVE
  Osteopontin (OPN) is upregulated in adipose tissue (AT) in obesity and contributes to subclinical inflammation, adipocyte dysfunction, and insulin resistance. OPN effects can be increased by cleavage by matrix metalloproteinases (MMP). This study aimed at investigating the presence of OPN cleavage products in human AT in obesity and their impact on adipocyte function and immunological blockade of these effects.
  
  
  METHODS
  AT of severely obese and control donors was investigated for OPN and MMP expression and the presence of OPN cleavage fragments. Primary adipocytes were isolated from human donors for in vitro investigation of cleaved OPN effects.
  
  
  RESULTS
  OPN and MMP-9 expression was highly correlated in AT from obese donors, and increased levels of cleaved OPN were detected in AT from obese individuals. The in vitro effect of OPN on adipocyte inflammation and insulin resistance was enhanced by protease cleavage, which could finally be blocked with a monoclonal antibody directed against the MMP cleavage site of OPN.
  
  
  CONCLUSIONS
  These findings show that MMP cleavage of OPN in AT occurs in obesity, thereby enhancing OPN's inflammatory and pro-diabetic activity on adipocytes. Specifically targeting MMP-cleaved OPN opens avenues for prevention and treatment of obesity-induced type 2 diabetes.
authors.affiliation: Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Leitner
authors.forename: Karina
authors.initials: K
authors.lastname: Schuch
authors.forename: Alexander
authors.initials: A
authors.lastname: Jürets
authors.forename: Bianca K
authors.initials: BK
authors.lastname: Itariu
authors.forename: Maike
authors.initials: M
authors.lastname: Keck
authors.forename: Viktor
authors.initials: V
authors.lastname: Grablowitz
authors.forename: Oskar C
authors.initials: OC
authors.lastname: Aszmann
authors.forename: Gerhard
authors.initials: G
authors.lastname: Prager
authors.forename: Günther
authors.initials: G
authors.lastname: Staffler
authors.forename: Maximilian
authors.initials: M
authors.lastname: Zeyda
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Stulnig
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009765:Obesity / Q000276:immunology* / Q000503:physiopathology / Q000517:prevention & control; D053495:Osteopontin / Q000378:metabolism*
chemical_list: D053495:Osteopontin; D020780:Matrix Metalloproteinase 9