Neutralization of Osteopontin Inhibits Obesity-Induced Inflammation and Insulin Resistance

  1. Thomas M. Stulnig1
  1. 1Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria;
  2. 2Clinical Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria;
  3. 3Ludwig Boltzmann Institute for Cancer Research, Medical University of Vienna, Vienna, Austria;
  4. 4Department of Pathology, Medical University of Vienna, Vienna, Austria.
  1. Corresponding author: Thomas M. Stulnig, thomas.stulnig{at}meduniwien.ac.at.

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.

RESEARCH DESIGN AND 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 NH2-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.

Footnotes

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    • Received March 17, 2009.
    • Accepted January 17, 2010.

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  1. Diabetes vol. 59 no. 4 935-946
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