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

Louise Grant, Kirsty D Shearer, Alicja Czopek, Emma K Lees, Carl Owen, Abdelali Agouni, James Workman, Cristina Martin-Granados, John V Forrester, Heather M Wilson, Nimesh Mody, Mirela Delibegovic

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)456-70
Number of pages15
JournalDiabetes
Volume63
Issue number2
DOIs
Publication statusPublished - Feb 2014

Keywords

  • Adipose Tissue, White
  • Animals
  • Cell Line
  • Dietary Fats
  • Drug-Induced Liver Injury
  • Endotoxemia
  • Gene Expression Regulation, Enzymologic
  • Glucose
  • Homeostasis
  • Hyperinsulinism
  • Inflammation
  • Interleukin-10
  • Janus Kinases
  • Lipopolysaccharides
  • Macrophages
  • Mice
  • Mice, Knockout
  • Myeloid Cells
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • STAT3 Transcription Factor
  • Signal Transduction
  • Spleen

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