Hepatic Oxidative Stress Promotes Insulin-STAT-5 Signaling and Obesity by Inactivating Protein Tyrosine Phosphatase N2

Gurzov, Esteban Nicolas; Tran, Melanie; Fernández‐Rojo, Manuel A.; Merry, Troy L.; Zhang, Xinmei; Xu, Yang; Fukushima, Atsushi; Waters, Michael J.; Watt, Matthew J.; Andrikopoulos, Sofianos; Neel, Benjamin G.; Tiganis, Tony

doi:10.1016/j.cmet.2014.05.011

Cited by 94 publications

(123 citation statements)

References 74 publications

(118 reference statements)

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“…Obesity is associated with elevated circulating free fatty acids (FFAs) (17), which induce oxidative stress by promoting the production of reactive oxygen species (ROS) to a level greater than their removal, and the high level of ROS is the main cause of insulin resistance (18,19). A high-fat diet is associated with a reduction in the hepatic levels of the antioxidant glutathione (GSH) and diminished activity of antioxidant enzymes, while the activity of some enzymes such as NADPH oxidase which produce ROS, is augmented (20,21).…”

Section: Pathogenesismentioning

confidence: 99%

Morbidity and mortality associated with obesity

Abdelaal

Roux

Docherty

2017

Annals of Translational Medicine

729

459

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Obesity and its repercussions constitute an important source of morbidity, impaired quality of life and its complications can have a major bearing on life expectancy. The present article summarizes the most important co-morbidities of obesity and their prevalence. Furthermore, it describes classification and grading systems that can be used to assess the individual and combined impact of co-morbid conditions on mortality risk. The literature was screened for assessment tools that can be deployed in the quantification of morbidity and mortality risk in individual patients. Thirteen specific domains have been identified that account for morbidity and mortality in obesity. Cardiovascular disease (CVD) and cancer account for the greatest mortality risk associated with obesity. The King's Criteria and Edmonton Obesity Staging System (EOSS) were identified as useful tools for the detection and monitoring of individual patient mortality risk in obesity care. The stark facts on the complications of obesity should be capitalized on to improve patient management and knowledge and referred to in the wider dissemination of public health messages aimed at improving primary prevention.

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Section: Pathogenesismentioning

confidence: 99%

Morbidity and mortality associated with obesity

Abdelaal

Roux

Docherty

2017

Annals of Translational Medicine

729

459

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“…FFAs induce oxidative stress (Nakamura et al 2009, Yuzefovych et al 2010, Gurzov et al 2014, which occurs when the rate of reactive oxygen species (ROS) production is greater than their removal (Evans et al 2002), and ROS cause insulin resistance (Hansen et al 1999). …”

Section: Introductionmentioning

confidence: 99%

Effect of N-acetyl-l-cysteine on insulin resistance caused by prolonged free fatty acid elevation

Pereira¹,

Shah²,

Fantus³

et al. 2015

Journal of Endocrinology

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Circulating free fatty acids (FFAs) are elevated in obesity and cause insulin resistance. The objective of the current study was to determine whether the antioxidant N-acetyl-L-cysteine (NAC) prevented hepatic and peripheral insulin resistance caused by prolonged elevation of plasma FFAs. Chronically cannulated Wistar rats received saline (SAL), Intralipid plus heparin (IH), IH plus NAC, or NAC i.v. infusion for 48 h. Insulin sensitivity was determined using the hyperinsulinemic-euglycemic clamp with tritiated glucose tracer. IH induced hepatic and peripheral insulin resistance (P!0.05). NAC co-infusion did not prevent insulin resistance in the liver, although it was able to prevent peripheral insulin resistance. Prolonged IH infusion did not appear to induce oxidative stress in the liver because hepatic content of protein carbonyl, malondialdehyde, and reduced to oxidized glutathione ratio did not differ across treatment groups. In alignment with our insulin sensitivity results, IH augmented skeletal muscle protein carbonyl content and this was prevented by NAC co-infusion. Taken together, our results indicate that oxidative stress mediates peripheral, but not hepatic, insulin resistance resulting from prolonged plasma FFA elevation. Thus, in states of chronic plasma FFA elevation, such as obesity, antioxidants may protect against peripheral but not hepatic insulin resistance.

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“…Probes are provided in Supplementary Table 2. PTP Oxidation, Immunoprecipitation, and Western Blotting Total (reversible and irreversible) PTP oxidation was assessed essentially as described previously (9). Briefly, PTP oxidation results in two pools of PTPs: oxidized (PTP-SOH; inactive) and reduced (PTP-S 2 ; active).…”

Section: Real-time Pcrmentioning

confidence: 99%

“…ROSmediated oxidation of the PTP active site Cys inhibits PTP activity and prevents substrate binding. Recent studies have established that PTP oxidation occurs in vivo under physiological and pathological conditions such as inflammation (6,8,9).The total serum antioxidant levels of patients with prediabetes and patients with T1D are reduced compared with age-matched controls (10,11). Furthermore, ROS and oxidative stress have been linked to b-cell cytotoxicity and are believed to be involved in pathology (12).…”

mentioning

confidence: 99%

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Inactivation of Protein Tyrosine Phosphatases Enhances Interferon Signaling in Pancreatic Islets

et al. 2015

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Type 1 diabetes (T1D) is the result of an autoimmune assault against the insulin-producing pancreatic b-cells, where chronic local inflammation (insulitis) leads to b-cell destruction. T cells and macrophages infiltrate into islets early in T1D pathogenesis. These immune cells secrete cytokines that lead to the production of reactive oxygen species (ROS) and T-cell invasion and activation. Cytokine-signaling pathways are very tightly regulated by protein tyrosine phosphatases (PTPs) to prevent excessive activation. Here, we demonstrate that pancreata from NOD mice with islet infiltration have enhanced oxidation/inactivation of PTPs and STAT1 signaling compared with NOD mice that do not have insulitis. Inactivation of PTPs with sodium orthovanadate in human and rodent islets and b-cells leads to increased activation of interferon signaling and chemokine production mediated by STAT1 phosphorylation. Furthermore, this exacerbated STAT1 activation-induced cell death in islets was prevented by overexpression of the suppressor of cytokine signaling-1 or inactivation of the BH3-only protein Bim. Together our data provide a mechanism by which PTP inactivation induces signaling in pancreatic islets that results in increased expression of inflammatory genes and exacerbated insulitis.Type 1 diabetes (T1D) is caused by progressive loss of pancreatic b-cells due to an autoimmune assault. Local inflammation and proinflammatory cytokines, particularly interferons (IFNs), play an important role in b-cell loss (1,2). IFN-g signal transduction involves activation of the tyrosine kinases Janus kinase (JAK) 1 and JAK2 that phosphorylate STAT1. These then dimerize, translocate to the nucleus, and bind g-activated sites of a diverse array of genes. Blocking activation of this transcriptional pathway protects islets from immune destruction (3-5). These data indicate that excessive activation of JAK/STAT signaling in islets during the inflammatory process contributes to b-cell dysfunction and death. Cytokine signaling results in the upregulation and release of factors by b-cells, such as chemokines, that attract immune cells and amplify the inflammatory process.Protein tyrosine phosphatases (PTPs) are a large superfamily of enzymes that dephosphorylate tyrosine phosphorylated proteins to oppose the actions of protein tyrosine kinases (6,7). PTPs play an important role in the development of both forms of diabetes (8). The architecture and low thiol pKa of the Cys residue in the active site of PTPs renders these proteins highly susceptible to oxidation by reactive oxygen species (ROS) (6,8). ROSmediated oxidation of the PTP active site Cys inhibits PTP activity and prevents substrate binding. Recent studies have established that PTP oxidation occurs in vivo under physiological and pathological conditions such as inflammation (6,8,9).The total serum antioxidant levels of patients with prediabetes and patients with T1D are reduced compared with age-matched controls (10,11). Furthermore, ROS and oxidative stress have been linked to b-cell c...

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Hepatic Oxidative Stress Promotes Insulin-STAT-5 Signaling and Obesity by Inactivating Protein Tyrosine Phosphatase N2

Cited by 94 publications

References 74 publications

Morbidity and mortality associated with obesity

Morbidity and mortality associated with obesity

Effect of N-acetyl-l-cysteine on insulin resistance caused by prolonged free fatty acid elevation

Inactivation of Protein Tyrosine Phosphatases Enhances Interferon Signaling in Pancreatic Islets

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