title: 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.
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.
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, College of Life Sciences and Medicine, Foresterhill Health Campus, Aberdeen, United Kingdom.
authors.forename: Louise
authors.initials: L
authors.lastname: Grant
authors.forename: Kirsty D
authors.initials: KD
authors.lastname: Shearer
authors.forename: Alicja
authors.initials: A
authors.lastname: Czopek
authors.forename: Emma K
authors.initials: EK
authors.lastname: Lees
authors.forename: Carl
authors.initials: C
authors.lastname: Owen
authors.forename: Abdelali
authors.initials: A
authors.lastname: Agouni
authors.forename: James
authors.initials: J
authors.lastname: Workman
authors.forename: Cristina
authors.initials: C
authors.lastname: Martin-Granados
authors.forename: John V
authors.initials: JV
authors.lastname: Forrester
authors.forename: Heather M
authors.initials: HM
authors.lastname: Wilson
authors.forename: Nimesh
authors.initials: N
authors.lastname: Mody
authors.forename: Mirela
authors.initials: M
authors.lastname: Delibegovic
mesh_terms: D052436:Adipose Tissue, White / Q000187:drug effects / Q000473:pathology; D000818:Animals; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury; D004041:Dietary Fats / Q000009:adverse effects*; D019446:Endotoxemia / Q000139:chemically induced; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D006946:Hyperinsulinism / Q000139:chemically induced*; D007249:Inflammation / Q000139:chemically induced* / Q000473:pathology; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000201:enzymology* / Q000502:physiology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D008070:Lipopolysaccharides; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016753:Interleukin-10; D053612:Janus Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D005947:Glucose