Protein tyrosine phosphatase-1B contributes to LPS-induced leptin resistance in male rats

Borges, Beatriz de Carvalho; Rorato, Rodrigo; Uchôa, Ernane Torres; Marangon, Paula Beatriz; Elias, Carol F.; Antunes‐Rodrigues, José

doi:10.1152/ajpendo.00094.2014

Cited by 17 publications

(6 citation statements)

References 53 publications

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“…Furthermore, PTP1B inhibition seems to pose a risk for hyperinflammation in case of a simultaneous infection, indicated by the increased PTP1B inhibition resulting in an extremely increased IL-8 release triggered by the combination of LPS and the PTP1B inhibitor. Accordingly, PTP1B has previously been described as an important negative regulator of LPS-induced inflammation in various cell types 49–51 , functioning as safety mechanism preventing hyperinflammation. If regular exposure to PTP1B inhibiting welding fumes could end in clinically relevant hyperinflammation as reaction to pulmonary or systemic infections is unclear and needs to be investigated.…”

Section: Discussionmentioning

confidence: 99%

The pro-inflammatory stimulus of zinc- and copper-containing welding fumes in whole blood assay via protein tyrosine phosphatase 1B inhibition

Bleidorn

Alamzad-Krabbe

Gerhards

et al. 2019

Sci Rep

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An asymptomatic systemic inflammation after exposure to zinc- and copper-containing welding fumes has been described as mild form of metal fume fever in recent studies. Since chronic systemic inflammation leads to a higher cardiovascular risk, examining the inflammation with the underlying pathomechanism is necessary to estimate and hopefully prevent long-term effects of welding. We established a whole blood assay to investigate the effects of zinc- and copper-containing welding fume particles on the blood immune response. Increased levels of IL-6, IL-8, TNFα and IL-1β determined after 24 hours of exposure indicated an acute systemic inflammatory reaction. In vitro increases of IL-6 were comparable to in vivo increases of serum IL-6 levels in a study with welding fume exposure of human subjects. Inhibition of PTP1B was identified as one pathway responsible for the effects of zinc- and copper-containing welding fumes and therefore welding fume fever. In conclusion, the whole blood assay is a reliable and feasible method to investigate effects of zinc- and copper-containing welding fumes on the immune system and as a surrogate for systemic inflammation and welding fume fever. Future research can utilize whole blood assays to reduce and partially replace human exposure studies for further investigations of welding fume fever.

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Section: Discussionmentioning

confidence: 99%

The pro-inflammatory stimulus of zinc- and copper-containing welding fumes in whole blood assay via protein tyrosine phosphatase 1B inhibition

Bleidorn

Alamzad-Krabbe

Gerhards

et al. 2019

Sci Rep

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“…This inhibits adipocyte synthesis, and thereby reduces body weight. Therefore, leptin plays a key role in regulating the physiological processes of food intake, glucose homeostasis, and energy intake and consumption [7,22,23].…”

Section: Introductionmentioning

confidence: 99%

Leptin Promotes White Adipocyte Browning by Inhibiting the Hh Signaling Pathway

Wang

Cao

et al. 2019

Cells

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Leptin is an important secretory protein that regulates the body’s intake and energy consumption, and the functions of the Hh signaling pathway related to white adipocyte browning are controversial. It has been reported that leptin plays a critical role in adipogenesis by regulating the Hh signaling pathway, but whether there is a functional relationship between leptin, the Hh signaling pathway, and adipocyte browning is not clear. In this research, mouse white pre-adipocytes were isolated to explore the influence of the Hh signal pathway and leptin during the process described above. This showed that leptin decreased high fat diet-induced obese mice body weight and inhibited the Hh signaling pathway, which suggested that leptin and the Hh signaling pathway have an important role in obesity. After activation of the Hh signaling pathway, significantly decreased browning fat-relative gene expression levels were recorded, whereas inhibition of the Hh signaling pathway significantly up-regulated the expression of these genes. Similarly, leptin also up-regulated the expression of these genes, and increased mitochondrial DNA content, but decreased the expression of Gli, the key transcription factors of the Hh signaling pathway. In short, the results show that leptin promotes white adipocyte browning through inhibiting the Hh signaling pathway. Overall, these results demonstrate that leptin serves as a potential intervention to decrease obesity by inhibiting the Hh signaling pathway.

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“…Chronic low-grade inflammation is associated with leptin and insulin resistance, which contributes to the establishment of obesity and its comorbidities, such as type 2 diabetes, cancer, and cardiovascular diseases [ 1 ]. We have previously demonstrated that low-grade inflammation induced by repeated injections of the Gram-negative bacterial lipopolysaccharide (6 daily doses of LPS) induces tolerance to the hypophagic effect of the endotoxin [ 2 , 3 ]. The endotoxin failure to reduce food consumption and body weight in LPS-tolerant rats is associated with unresponsiveness to leptin to phosphorylate the signal transduction and activator of transcription 3 (pSTAT3) protein in the hypothalamic nuclei crucial for the control of the energy homeostasis, such as the paraventricular (PVN) and arcuate (ARC) nuclei [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

LPS-Induced Low-Grade Inflammation Increases Hypothalamic JNK Expression and Causes Central Insulin Resistance Irrespective of Body Weight Changes

Rorato

Borges

Uchôa

et al. 2017

IJMS

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Metabolic endotoxemia contributes to low-grade inflammation in obesity, which causes insulin resistance due to the activation of intracellular proinflammatory pathways, such as the c-Jun N-terminal Kinase (JNK) cascade in the hypothalamus and other tissues. However, it remains unclear whether the proinflammatory process precedes insulin resistance or it appears because of the development of obesity. Hypothalamic low-grade inflammation was induced by prolonged lipopolysaccharide (LPS) exposure to investigate if central insulin resistance is induced by an inflammatory stimulus regardless of obesity. Male Wistar rats were treated with single (1 LPS) or repeated injections (6 LPS) of LPS (100 μg/kg, IP) to evaluate the phosphorylation of the insulin receptor substrate-1 (IRS1), Protein kinase B (AKT), and JNK in the hypothalamus. Single LPS increased the expression of pIRS1, pAKT, and pJNK, whereas the repeated LPS treatment failed to recruit pIRS1 and pAKT. The 6 LPS treated rats showed increased total JNK and pJNK. The 6 LPS rats became unresponsive to the hypophagic effect induced by central insulin administration (12 μM/5 μL, ICV). Prolonged exposure to LPS (24 h) impaired the insulin-induced AKT phosphorylation and the translocation of the transcription factor forkhead box protein O1 (FoxO1) from the nucleus to the cytoplasm of the cultured hypothalamic GT1-7 cells. Central administration of the JNK inhibitor (20 μM/5 μL, ICV) restored the ability of insulin to phosphorylate IRS1 and AKT in 6 LPS rats. The present data suggest that an increased JNK activity in the hypothalamus underlies the development of insulin resistance during prolonged exposure to endotoxins. Our study reveals that weight gain is not mandatory for the development of hypothalamic insulin resistance and the blockade of proinflammatory pathways could be useful for restoring the insulin signaling during prolonged low-grade inflammation as seen in obesity.

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Protein tyrosine phosphatase-1B contributes to LPS-induced leptin resistance in male rats

Cited by 17 publications

References 53 publications

The pro-inflammatory stimulus of zinc- and copper-containing welding fumes in whole blood assay via protein tyrosine phosphatase 1B inhibition

The pro-inflammatory stimulus of zinc- and copper-containing welding fumes in whole blood assay via protein tyrosine phosphatase 1B inhibition

Leptin Promotes White Adipocyte Browning by Inhibiting the Hh Signaling Pathway

LPS-Induced Low-Grade Inflammation Increases Hypothalamic JNK Expression and Causes Central Insulin Resistance Irrespective of Body Weight Changes

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