Retracted: Modulation of hypothalamic PTP1B in the TNF‐α‐induced insulin and leptin resistance

Picardi, Paty Karoll; Caricilli, Andréa M.; Abreu, Lélia Lelis Ferreira de; Carvalheira, José B.C.; Velloso, Lı́cio A.; Saad, Mário José Abdalla

doi:10.1016/j.febslet.2010.05.064

Cited by 26 publications

(36 citation statements)

References 36 publications

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“…Indeed, in a mouse model, Vijay-Kumar et al (15) reported that TLR-5 receptor impairment, involved in the bacterial flagellin recognition, led to a "human metabolic syndrome gut microbiota phenotype, " associated with low-grade inflammatory signals. In another study (16), the authors observed a metabolic syndrome after colonization of TLR-2 GF deficient mice, protected from diet-induced insulin resistance. The TLR-2 deficient mice became resistant to insulin and therefore obese, suggesting a correlation with the increased fat storage or with the augmented levels of gastrointestinal lipopolysaccharide (LPS) permeability and absorption.…”

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confidence: 98%

The human gut microbiota: a dynamic interplay with the host from birth to senescence settled during childhood

et al. 2014

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confidence: 98%

The human gut microbiota: a dynamic interplay with the host from birth to senescence settled during childhood

et al. 2014

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“…We observed that single or repeated LPS treatment increased the PTP1B expression with a high colocalization with LepRbexpressing neurons in the hypothalamus. Changes in PTP1B expression have been shown to be induced by molecules such as tumor necrosis factor (TNF)␣ and nuclear factor-B (NF-B) (20,29,34,36,53), and LPS is known to induce the production of these molecules. Picardi et al (36) have demonstrated that central infusion of TNF␣ increased PTP1B protein expression and attenuated leptin sensitivity in the hypothalamus.…”

Section: E45 Leptin Resistance Induced By Long-term Exposure To Lpsmentioning

confidence: 99%

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

Borges

Rorato

Uchôa

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Borges BC, Rorato RC, Uchoa ET, Marangon PB, Elias CF, Antunes-Rodrigues J, Elias LL. Protein tyrosine phosphatase-1B contributes to LPS-induced leptin resistance in male rats. Am J Physiol Endocrinol Metab 308: E40 -E50, 2015. First published October 28, 2014 doi:10.1152/ajpendo.00094.2014.-Leptin resistance is induced by the feedback inhibitors tyrosine phosphatase-1B (PTP1B) and decreased Src homology 2 domain-containing tyrosine phosphatase-2 (SHP-2) signaling. To investigate the participation of PTP1B and SHP-2 in LPS-induced leptin resistance, we injected repeated (6-LPS) intraperitoneal LPS doses (100 g/kg ip) for comparison with a single (1-LPS) treatment and evaluated the expression of SHP-2, PTP1B, p-ERK1/2, and p-STAT3 in the hypothalamus of male Wistar rats. The single LPS treatment increased the expression of p-STAT3 and PTP1B but not SHP-2. The repeated LPS treatment reduced SHP-2, increased PTP1B, and did not change p-STAT3. We observed that the PTP1B expression induced by the endotoxin was highly colocalized with leptin receptor cells in the hypothalamus of LepRb-IRESCre-tdTomato reporter mice. The single, but not the repeated, LPS treatment decreased the food intake and body weight. Leptin had no stimulatory effect on the hypophagia, body weight loss, or pSTAT3 expression in 6-LPS rats, indicating leptin unresponsiveness. Notably, the PTP1B inhibitor (3.0 nmol/rat in 5 l icv) restored the LPSinduced hypophagia in 6-LPS rats and restored the ability of leptin to reduce food intake and body weight as well as to phosphorylate STAT3 in the arcuate, paraventricular, and ventromedial nuclei of the hypothalamus. The present data suggest that an increased PTP1B expression in the hypothalamus underlies the development of leptin resistance during repeated exposure to LPS. Our findings contribute to understanding the mechanisms involved in leptin resistance during low-grade inflammation as seen in obesity. leptin resistance; endotoxemia; protein tyrosine phosphatase-1B; Src homology 2 domain-containing tyrosine phosphatase-2; extracellular signal-regulated kinases INFLAMMATION HAS BEEN DEMONSTRATED to be a common underlying cause of many obesity-associated conditions, such as diabetes and atherosclerosis (13,30,37,48). Rodent models of the obesity induced by a fat-enriched diet show enhancement of inflammatory cytokine secretion (37) and increased hypothalamic inflammatory signaling (44). Changes in gut microbiota are crucial factors in the development of obesity. Cani et al. (9) reported that high-fat feeding in mice augments plasma lipopolysaccharide (LPS) from gram-negative bacteria at a concentration sufficient to increase body weight and inflammation. In rats, the inflammation triggered by LPS and the subsequent activation of Toll-like receptor 4 (TLR4) has a determinant role in the development of the obese phenotype in response to high-fat/high-calorie food intake (14). Interestingly, exogenous long-term LPS infusion (300 g·kg Ϫ1 ·day Ϫ1for 4 wk) in normal-diet-fed mice caused a metabolic response t...

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“…Moreover, dietinduced induction in proinflammatory cytokines triggers an immediate response in non-neuronal hypothalamic cells (microglial and astroglial populations) [33,36,37]. Corroborating a role for proinflammatory cytokines in leptin signalling pathology, central administration of TNF-α impairs leptin sensitivity, possibly by increasing the levels of SOCS3 and PTP1B, which act as negative regulators of leptin receptor signalling [9,11,38]. Although causality is not clear, there is considerable evidence to support the existence of a vicious cycle between excess nutrients, hypothalamic inflammation, leptin resistance and obesity [39].…”

Section: Targeting Leptin Responsiveness With Pharmacologymentioning

confidence: 99%

“…Indeed, preclinical studies have identified several 'leptin sensitisers', that may hold therapeutic promise. These leptin sensitisers target distinct neuroendocrine systems, all of which have been linked to leptin signalling pathology, including endoplasmic reticulum (ER) stress [8], hypothalamic inflammation [9] and multiple nodes of the leptin signalling cascade [10][11][12][13]. In addition, a growing body of evidence suggests that gastrointestinalderived peptides and a series of already approved pharmacotherapies can amplify the weight-lowering actions of exogenous leptin [14][15][16][17][18][19], re-positioning leptin as a relevant agent in combination therapies for the treatment of obesity.…”

Section: Introductionmentioning

confidence: 99%

Renaissance of leptin for obesity therapy

et al. 2016

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Diet-induced obesity and its metabolic comorbidities constitute an overwhelming health crisis and there is an urgent need for safe and effective pharmacological interventions. Being largely shelved for decades, scientists are now revisiting the antiobesity virtues of leptin. Whereas it remains evident that leptin as a stand-alone therapy is not an effective approach, the potential for employing sensitising pharmacology to unleash the weight-lowering properties of leptin has injected new hope into the field. Fascinatingly, these leptin-sensitising agents seem to act via distinct metabolic pathways and may thus, in parallel with their clinical development, serve as important research tools to progress our understanding of the molecular, physiological and behavioural pathways underlying energy homeostasis and obesity pathophysiology. This review summarises a presentation given at the 'Is leptin coming back?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium

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Retracted: Modulation of hypothalamic PTP1B in the TNF‐α‐induced insulin and leptin resistance

Cited by 26 publications

References 36 publications

The human gut microbiota: a dynamic interplay with the host from birth to senescence settled during childhood

The human gut microbiota: a dynamic interplay with the host from birth to senescence settled during childhood

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

Renaissance of leptin for obesity therapy

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