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Media type:
E-Article
Title:
Neutralization of Osteopontin Inhibits Obesity-Induced Inflammation and Insulin Resistance
Contributor:
Kiefer, Florian W.;
Zeyda, Maximilian;
Gollinger, Karina;
Pfau, Birgit;
Neuhofer, Angelika;
Weichhart, Thomas;
Säemann, Marcus D.;
Geyeregger, René;
Schlederer, Michaela;
Kenner, Lukas;
Stulnig, Thomas M.
imprint:
American Diabetes Association, 2010
Published in:Diabetes
Language:
English
DOI:
10.2337/db09-0404
ISSN:
0012-1797;
1939-327X
Origination:
Footnote:
Description:
<jats:sec>
<jats:title>OBJECTIVE</jats:title>
<jats:p>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.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>RESEARCH DESIGN AND METHODS</jats:title>
<jats:p>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.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>RESULTS</jats:title>
<jats:p>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.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>CONCLUSIONS</jats:title>
<jats:p>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.</jats:p>
</jats:sec>