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

Diabetes. 2014 Feb;63(2):456-70. doi: 10.2337/db13-0885. Epub 2013 Nov 1.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, White / drug effects
  • Adipose Tissue, White / pathology
  • Animals
  • Cell Line
  • Chemical and Drug Induced Liver Injury
  • Dietary Fats / adverse effects*
  • Endotoxemia / chemically induced
  • Gene Expression Regulation, Enzymologic / physiology
  • Glucose / metabolism
  • Homeostasis
  • Hyperinsulinism / chemically induced*
  • Inflammation / chemically induced*
  • Inflammation / pathology
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism
  • Janus Kinases / genetics
  • Janus Kinases / metabolism
  • Lipopolysaccharides / toxicity*
  • Macrophages / metabolism
  • Mice
  • Mice, Knockout
  • Myeloid Cells / enzymology*
  • Myeloid Cells / physiology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism*
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Spleen / cytology
  • Spleen / metabolism


  • Dietary Fats
  • Lipopolysaccharides
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Interleukin-10
  • Janus Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Glucose