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⇑ and
- Mirela Delibegovic⇑
- Institute of Medical Sciences, University of Aberdeen, College of Life Sciences and Medicine, Foresterhill Health Campus, Aberdeen, United Kingdom
- Corresponding authors: Mirela Delibegovic, , and Nimesh Mody, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0885/-/DC1.
- Received June 5, 2013.
- Accepted October 28, 2013.
- © 2014 by the American Diabetes Association.
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