title: Neutralization of osteopontin inhibits obesity-induced inflammation and insulin resistance.
abstract: OBJECTIVE
  Obesity is associated with a state of chronic low-grade inflammation mediated by immune cells that are primarily located to adipose tissue and liver. The chronic inflammatory response appears to underlie obesity-induced metabolic deterioration including insulin resistance and type 2 diabetes. Osteopontin (OPN) is an inflammatory cytokine, the expression of which is strongly upregulated in adipose tissue and liver upon obesity. Here, we studied OPN effects in obesity-induced inflammation and insulin resistance by targeting OPN action in vivo.
  
  
  METHODS
  C57BL/6J mice were fed a high-fat diet to induce obesity and were then intravenously treated with an OPN-neutralizing or control antibody. Insulin sensitivity and inflammatory alterations in adipose tissue and liver were assessed.
  
  
  RESULTS
  Interference with OPN action by a neutralizing antibody for 5 days significantly improved insulin sensitivity in diet-induced obese mice. Anti-OPN treatment attenuated liver and adipose tissue macrophage infiltration and inflammatory gene expression by increasing macrophage apoptosis and significantly reducing c-Jun NH(2)-terminal kinase activation. Moreover, we report OPN as a novel negative regulator for the activation of hepatic signal transducer and activator of transcription 3 (STAT3), which is essential for glucose homeostasis and insulin sensitivity. Consequently, OPN neutralization decreased expression of hepatic gluconeogenic markers, which are targets of STAT3-mediated downregulation.
  
  
  CONCLUSIONS
  These findings demonstrate that antibody-mediated neutralization of OPN action significantly reduces insulin resistance in obesity. OPN neutralization partially decreases obesity-associated inflammation in adipose tissue and liver and reverses signal transduction related to insulin resistance and glucose homeostasis. Hence, targeting OPN could provide a novel approach for the treatment of obesity-related metabolic disorders.
authors.affiliation: Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Florian W
authors.initials: FW
authors.lastname: Kiefer
authors.forename: Maximilian
authors.initials: M
authors.lastname: Zeyda
authors.forename: Karina
authors.initials: K
authors.lastname: Gollinger
authors.forename: Birgit
authors.initials: B
authors.lastname: Pfau
authors.forename: Angelika
authors.initials: A
authors.lastname: Neuhofer
authors.forename: Thomas
authors.initials: T
authors.lastname: Weichhart
authors.forename: Marcus D
authors.initials: MD
authors.lastname: Säemann
authors.forename: René
authors.initials: R
authors.lastname: Geyeregger
authors.forename: Michaela
authors.initials: M
authors.lastname: Schlederer
authors.forename: Lukas
authors.initials: L
authors.lastname: Kenner
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Stulnig
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000918:Antibody Specificity; D001786:Blood Glucose / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology; D005434:Flow Cytometry; D007074:Immunoglobulin G / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D007328:Insulin / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D053495:Osteopontin / Q000276:immunology*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D001786:Blood Glucose; D004041:Dietary Fats; D007074:Immunoglobulin G; D007328:Insulin; D008055:Lipids; C506896:Spp1 protein, mouse; D014280:Triglycerides; D053495:Osteopontin