Neutralization of osteopontin inhibits obesity-induced inflammation and insulin resistance

Diabetes. 2010 Apr;59(4):935-46. doi: 10.2337/db09-0404. Epub 2010 Jan 27.


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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / pharmacology
  • Antibody Specificity
  • Blood Glucose / metabolism
  • Dietary Fats / pharmacology
  • Flow Cytometry
  • Immunoglobulin G / pharmacology
  • In Situ Nick-End Labeling
  • Inflammation / blood
  • Inflammation / immunology
  • Inflammation / pathology
  • Inflammation / prevention & control*
  • Insulin / physiology
  • Insulin Resistance / physiology*
  • Lipids / blood
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Obesity / blood
  • Obesity / immunology
  • Obesity / pathology
  • Obesity / physiopathology*
  • Osteopontin / immunology*
  • Triglycerides / metabolism


  • Antibodies, Neutralizing
  • Blood Glucose
  • Dietary Fats
  • Immunoglobulin G
  • Insulin
  • Lipids
  • Spp1 protein, mouse
  • Triglycerides
  • Osteopontin