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Cited by 200Adipokines, Inflammation, and Metabolic DiseasesBone and Dental Protein StudiesBone Metabolism and Diseases

Neutralization of Osteopontin Inhibits Obesity-Induced Inflammation and Insulin Resistance

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Kiefer, Florian W., Zeyda, Maximilian, Gollinger, Karina, Pfau, Birgit, Neuhofer, Angelika, Weichhart, Thomas, Säemann, Marcus D., Geyeregger, René +3 more·2010·Diabetes
DOI 10.2337/db09-0404PMC PMC2844841
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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.

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Authors
Kiefer, F. W., Zeyda, M., Gollinger, K., Pfau, B., Neuhofer, A., Weichhart, T., Säemann, M. D., Geyeregger, R., Schlederer, M., Kenner, L., & Stulnig, T. M.
Affiliations
  • Medical University of Vienna (AT)
  • Ludwig Boltzmann Institute for Cancer Research (AT)
Corresponding author
Stulnig, Thomas M.
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2010-01-27
Volume
59
Issue
4
Pages
935-946
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db09-0404
PMC
PMC2844841
OpenAlex
W2149494021
Cited by
200
References
5
Citations by year
2026: 4 · 2025: 3 · 2024: 11 · 2023: 13 · 2022: 13 · 2021: 12 · 2020: 11 · 2019: 14 · 2018: 14 · 2017: 11 · 2016: 21 · 2015: 13 · 2014: 18 · 2013: 19 · 2012: 12
FWCI
9.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • European Commission (201608)
  • Austrian Science Fund (W1205, P 18776)
Topics
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Rheumatology › Bone and Dental Protein Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
Keywords
osteopontin, obesity, insulin resistance, inflammation, adipose tissue macrophages, hepatic macrophages, STAT3, c-Jun N-terminal kinase, gluconeogenesis, glucose homeostasis, type 2 diabetes, high-fat diet, macrophage apoptosis
MeSH terms
Animals, Antibody Specificity, Blood Glucose, Dietary Fats, Flow Cytometry, Immunoglobulin G, Inflammation, Insulin, Insulin Resistance, Lipids, Liver, Mice, Inbred C57BL, Obesity, Triglycerides, In Situ Nick-End Labeling, Mice, Osteopontin, Antibodies, Neutralizing

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