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.

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 five 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 novel negative regulator for the activation of hepatic 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.