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 wholebody 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 marrowderived macrophages (BMDMs) displayed increased interleukin (IL)-10 mRNA expression, with a concomitant decrease in TNF-a 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 LPSinduced 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 antiinflammatory and antidiabetic target in obesity.

Opposite Cross-Talk by Oleate and Palmitate on Insulin Signaling in Hepatocytes through Macrophage Activation

“…Because no differences in IL10 levels were found between macrophages loaded with oleate or BSA, our data pinpoint first LTB 4 as one of the macrophagesecreted lipid species that is decreased by oleate, leading to a positive effect in the macrophage-hepatocyte axis and, second, PTP1B as a critical node of the insulin signaling that is modulated by levels of LTB 4 via NFB. Although PTP1B has been involved in obesity and inflammation (45,65,66), this is the first study showing the modulation of PTP1B protein levels by a macrophage-derived lipid product from oleate because reduced levels of LTB 4 in CM-O paralleled with decreased PTP1B and enhancement of insulin-mediated IR tyrosine phosphorylation in hepatocytes. These data might be of relevance because PTP1B has emerged as a therapeutic target against obesity-mediated insulin resistance by its ability to regulate peripheral (muscle and liver) insulin sensitivity (65,(67)(68)(69)(70)(71)(72) as well as the central control of appetite and energy expenditure (45,73,74).…”

Quercetin prevents alcohol‑induced liver injury through targeting of PI3K/Akt/nuclear factor‑κB and STAT3 signaling pathway

“…Several research groups have demonstrated that TNF-α antibody therapy can prevent alcohol-induced liver injury in rats. Clinical experimental researches suggest that apoptosis of hepatocytes exists in ALD, and studies show the inhibition of hepatocyte apoptosis can relieve alcohol-induced liver injury in experimental animals (25). Pathologic studies show oxidative stress and hepatocyte apoptosis are involved in ALD cells apoptosis.…”

“…TNF-α and other inflammatory factors cause liver injury, and IL-6, IL-10 and others can protect the liver through inflammatory response (25). IL-6 up-regulates the expression of multiple anti-injury genes in liver cells by activating STAT-3 pathway; IL-10 inhibits hepatic inflammatory response by activating STAT3 in Kupffer cells (25).…”

“…IL-6 up-regulates the expression of multiple anti-injury genes in liver cells by activating STAT-3 pathway; IL-10 inhibits hepatic inflammatory response by activating STAT3 in Kupffer cells (25). The imbalance and re-balance process of proinflammatory and anti-inflammatory factors is the development and regression of ALD (28).…”

Pancreatic Protein Tyrosine Phosphatase 1B Deficiency Exacerbates Acute Pancreatitis in Mice

“…49 On the other hand, myeloid cellespecific PTP1B deficiency protects against high-fat diete and lipopolysaccharide-induced inflammation. 50 The reason(s) for these differences is not apparent and could depend on the experimental systems and/or regulation of inflammatory signaling by PTP1B in a stimulus/tissue-dependent manner. At any rate, given the current findings, it is reasonable to stipulate that the effects of pancreatic PTP1B deficiency during experimental AP could be mediated, at least partly, through exacerbation of the inflammatory response.…”