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Cited by 76Protein Tyrosine PhosphatasesAdipokines, Inflammation, and Metabolic DiseasesCytokine Signaling Pathways and Interactions

Myeloid-cell protein tyrosine phosphatase-1B deficiency in mice protects against high-fat diet and lipopolysaccharide-induced inflammation, hyperinsulinemia, and endotoxemia through an IL-10 STAT3-dependent mechanism

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Grant, Louise, Shearer, Kirsty D., Czopek, Alicja, Lees, Emma K., Owen, Carl, Agouni, Abdelali, Workman, James, Martin-Granados, Cristina +4 more·2014·Diabetes
DOI 10.2337/db13-0885
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Abstract

Protein tyrosine phosphatase-1B (PTP1B) negatively regulates insulin and leptin signaling, rendering it an attractive drug target for treatment of obesity-induced insulin resistance. However, some studies suggest caution when targeting macrophage PTP1B, due to its potential anti-inflammatory role. We assessed the role of macrophage PTP1B in inflammation and whole-body metabolism using myeloid-cell (LysM) PTP1B knockout mice (LysM PTP1B). LysM PTP1B mice were protected against lipopolysaccharide (LPS)-induced endotoxemia and hepatic damage associated with decreased proinflammatory cytokine secretion in vivo. In vitro, LPS-treated LysM PTP1B bone marrow–derived macrophages (BMDMs) displayed increased interleukin (IL)-10 mRNA expression, with a concomitant decrease in TNF-α mRNA levels. These anti-inflammatory effects were associated with increased LPS- and IL-10–induced STAT3 phosphorylation in LysM PTP1B BMDMs. Chronic inflammation induced by high-fat (HF) feeding led to equally beneficial effects of macrophage PTP1B deficiency; LysM PTP1B mice exhibited improved glucose and insulin tolerance, protection against LPS-induced hyperinsulinemia, decreased macrophage infiltration into adipose tissue, and decreased liver damage. HF-fed LysM PTP1B mice had increased basal and LPS-induced IL-10 levels, associated with elevated STAT3 phosphorylation in splenic cells, IL-10 mRNA expression, and expansion of cells expressing myeloid markers. These increased IL-10 levels negatively correlated with circulating insulin and alanine transferase levels. Our studies implicate myeloid PTP1B in negative regulation of STAT3/IL-10–mediated signaling, highlighting its inhibition as a potential anti-inflammatory and antidiabetic target in obesity.

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  • IL-10 protects against high-fat diet-induced inflammation and improves glucose tolerance through activation of STAT3.

    “IL-10 protects against high-fat diet–induced inflammation and improves glucose tolerance through the activation of STAT3 (Grant et al., 2014).”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Grant et al., 2014

    The glucose-homeostasis Results report improved glucose tolerance and reduced adipose inflammation in high-fat-fed mice lacking myeloid PTP1B. The Discussion proposes a STAT3-dependent expansion of IL-10-secreting cells as the mechanism, but presents that mechanism as postulated; it does not establish that IL-10 itself caused the improved glucose tolerance through STAT3 activation. Page numbers are unavailable in our copy. (LLM, conf=0.86)

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Authors
Grant, L., Shearer, K. D., Czopek, A., Lees, E. K., Owen, C., Agouni, A., Workman, J., Martin-Granados, C., Forrester, J. V., Wilson, H. M., Mody, N., & Delibegovic, M.
Affiliations
  • University of Aberdeen (GB)
  • Institute of Medical Sciences, University of Aberdeen, College of Life Sciences and Medicine, Foresterhill Health Campus, Aberdeen, United Kingdom
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2014-01-16
Volume
63
Issue
2
Pages
456-470
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db13-0885
OpenAlex
W2101798805
Cited by
76
References
47
Citations by year
2026: 6 · 2025: 1 · 2024: 6 · 2023: 4 · 2022: 4 · 2021: 4 · 2020: 6 · 2019: 6 · 2018: 3 · 2017: 17 · 2016: 6 · 2015: 5 · 2014: 8
FWCI
2.83
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Hope's Institutional Research Archive (Liverpool Hope University) (acceptedVersion)
  • Aberdeen University Research Archive (Aberdeen University) (submittedVersion)
  • Open Research (University of Surrey) (submittedVersion)
  • Surrey Research Insight Open Access (The University of Surrey) (submittedVersion)
Funders
  • Eli Lilly and Company
  • University of Pennsylvania
  • University of Dundee
  • British Heart Foundation (PG/11/8/28703)
  • European Foundation for the Study of Diabetes
  • University of Toronto
  • Biotechnology and Biological Sciences Research Council (1091530)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
PTP1B, macrophages, STAT3 phosphorylation, IL-10, endotoxemia, lipopolysaccharide-induced inflammation, high-fat diet, insulin resistance, hyperinsulinemia, liver injury, adipose tissue macrophage infiltration, TNF-α, obesity, anti-inflammatory therapy
MeSH terms
Animals, Cell Line, Dietary Fats, Glucose, Homeostasis, Hyperinsulinism, Inflammation, Lipopolysaccharides, Macrophages, Spleen, Signal Transduction, Gene Expression Regulation, Enzymologic, Interleukin-10, Mice, Knockout, Endotoxemia, Myeloid Cells, STAT3 Transcription Factor, Mice, Adipose Tissue, White, Janus Kinases, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Chemical and Drug Induced Liver Injury

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