Deficiency of PTP1B Attenuates Hypothalamic Inflammation via Activation of the JAK2-STAT3 Pathway in Microglia

Tsunekawa, Taku; Banno, Ryoichi; Mizoguchi, Akira; Sugiyama, Mariko; Tominaga, Takashi; Onoue, Takeshi; Hagiwara, Daisuke; Ito, Yoshihiro; Iwama, Shintaro; Goto, Motomitsu; Suga, Hidetaka; Sugimura, Yoshihisa; Arima, Hiroshi

doi:10.1016/j.ebiom.2017.01.007

Cited by 57 publications

(38 citation statements)

References 53 publications

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“…STATs are highly associated with the expression of proinflammatory cytokines [33]. In this study, we found that DSS exposure markedly reduced mRNA abundance of STAT3 in Caco-2 and HT-29 cells compared with the control group (P<0.05) (Fig.…”

Section: Mir-135a Mimic Activated Stat Signal In Caco-2 and Ht-29 Cellsmentioning

confidence: 50%

miR-135a Protects Dextran Sodium Sulfate-Induced Inflammation in Human Colorectal Cell Lines by Activating STAT3 Signal

Zhang

Liu

Shang

et al. 2018

Cell Physiol Biochem

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Background/Aims: miR-135a is reduced in several cancers and has been suggested to mediate immune and inflammatory responses. However, the effect of miR-135a on inflammatory bowel diseases was obscure. This study firstly attempted to investigate the hypothesis that miR-135a alleviates dextran sodium sulfate (DSS)-induced inflammation in colonic cells and potential mechanisms are also studied. Methods: Caco-2 and HT-29 cells in this study were treated with DSS, miR-135a mimic, and S3I-201, and then CKK-8 assay was used to test cell viability. Expressions of miR-135a, cytokines, and signal transducers and activators of transcription factors (STATs) were determined by RT-PCR. Also, cytokine productions were further tested by using ELISA kits. Activation or inactivation of STAT3 signal was validated by western blotting analysis. Results: The results showed that DSS markedly downregulated miR-135a expression (P< 0.05) and induced inflammatory response in Caco-2 and HT-29 cells evidenced by the up regulations and productions of interleukin-1β (IL-1β) and tumor necrosis factor-ɑ (TNF-ɑ) (P< 0.05). Transfection with miR-135a mimic significantly alleviated DSS-induced upregulation and productions of IL-1β and TNF-ɑ in Caco-2 and HT-29 cells (P< 0.05). STATs were analyzed and miR-135a mimic treatment reversed STAT3 downregulation in DSS-challenged Caco-2 and HT-29 cells compared with the mimic control (P< 0.05). Also, STAT3 phosphorylation was inhibited in DSS-challenged Caco-2 cells and miR-135a mimic activated STAT3 signal (P< 0.05). S3I-201, an inhibitor of STAT3 signal, further used to inactivate STAT3 signal and the results showed that S3I-201 blocked the anti-inflammatory effect of miR-135a mimic on Caco-2 and HT-29 cells evidenced by the lowered expressions and productions of proinflammatory cytokines ((IL-1β and TNF-ɑ) (P< 0.05). Conclusion: Our results indicated that miR-135a alleviated DSS-induced inflammation and activated STAT3 signal in colonic cells. Inhibition of STAT3 reversed the anti-inflammatory function of miR-135a by regulating proinflammatory cytokines. Thus, STAT3 signal might serve, at least in part, as the potential mechanism of miR-135a-mediated anti-inflammatory effect in colonic cells.

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Section: Mir-135a Mimic Activated Stat Signal In Caco-2 and Ht-29 Cellsmentioning

confidence: 50%

miR-135a Protects Dextran Sodium Sulfate-Induced Inflammation in Human Colorectal Cell Lines by Activating STAT3 Signal

Zhang

Liu

Shang

et al. 2018

Cell Physiol Biochem

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“…It has been also shown that PTP1B contributes to hypothalamic inflammation and leptin resistance in rodents fed a HFD . As a matter of fact, PTP1B −/− mice exhibit decreased TNF‐alpha expression, accompanied by increased interleukin‐10 mRNA levels in the hypothalamus, even under HFD‐feeding . Notably, TNF‐alpha has been shown to increase PTP1B expression in hypothalamic organotypic cultures in a dose and time‐dependent fashion .…”

Section: Discussionmentioning

confidence: 97%

“…41 As a matter of fact, PTP1B −/− mice exhibit decreased TNF-alpha expression, accompanied by increased interleukin-10 mRNA levels in the hypothalamus, even under HFD-feeding. 42 Notably, TNF-alpha has been shown to increase PTP1B expression in hypothalamic organotypic cultures in a dose and time-dependent fashion. 43 Nevertheless, despite PTP1B has been consistently shown to mediate insulin and leptin resistance in response to proinflammatory signals including endoplasmic reticulum stress, aging and TNF-alpha, there is still scant evidence regarding the benefit of using PTP1B and TNF-alpha-specific inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Infliximab ameliorates tumor necrosis factor‐alpha‐induced insulin resistance by attenuating PTP1B activation in 3T3L1 adipocytes in vitro

et al. 2018

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Insulin resistance is the inability to respond to insulin and is considered a key pathophysiological factor in the development of type 2 diabetes. Tumor necrosis factor-alpha (TNF-alpha) can directly contribute to insulin resistance by disrupting the insulin signalling pathway via protein-tyrosine phosphatase 1B (PTP1B) activation, especially in adipocytes. Infliximab (Remicade ) is a TNF-alpha-neutralizing antibody that has not been fully studied in insulin resistance. We investigated the effect of infliximab on TNF-alpha-induced insulin resistance in 3T3L1 adipocytes in vitro, and examined the possible molecular mechanisms involved. Once differentiated, adipocytes were cultured with 5 mmol L 2-deoxy-D-glucose- H and stimulated twice with 2 μmol L insulin, in the presence or absence of 5 ng/mL TNF-alpha and/or 10 ng/mL infliximab. Glucose uptake was measured every 20 minutes for 2 hour, and phosphorylated forms of insulin receptor (IR), insulin receptor substrate-2 (IRS-2), protein kinase B (AKT) and PTP1B were determined by Western blotting. TNF-alpha-treated adipocytes showed a significant 64% decrease in insulin-stimulated glucose uptake as compared with control cells, whereas infliximab reversed TNF-alpha actions by significantly improving glucose incorporation. Although IR phosphorylation remained unaltered, TNF-alpha was able to increase PTP1B activation and decrease phosphorylation of IRS-2 and AKT. Notably, infliximab restored phosphorylation of IRS-2 and AKT by attenuating PTP1B activation. This work demonstrates for the first time that infliximab ameliorates TNF-alpha-induced insulin resistance in 3T3L1 adipocytes in vitro by restoring the insulin signalling pathway via PTP1B inhibition. Further clinical research is needed to determine the potential benefit of using infliximab for treating insulin resistance in patients.

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“…Inflammation and the hyperleptinemia in obesity are known to drive reactive gliosis, endoplasmic reticulum (ER) stress and the expression of negative regulators of insulin signalling, such as SOCS3, PTP1B and TCPTP within the hypothalamus (Figure b3). The hyperleptinaemia seen in obesity is considered to increase the hypothalamic expression of TCPTP, PTP1B and SOCS3, whereas ER stress and the obesity‐associated inflammation drives the expression of PTP1B and SOCS3 . These negative regulators may be instrumental in the initiation/exacerbation and/or maintenance of cellular leptin and insulin resistance (Figure b3) .…”

Section: Insulin Resistance and Metabolic Diseasementioning

confidence: 99%

“…The hyperleptinaemia seen in obesity is considered to increase the hypothalamic expression of TCPTP, PTP1B and SOCS3, whereas ER stress and the obesity-associated inflammation drives the expression of PTP1B and SOCS3. 91,92,[202][203][204][205][206] These negative regulators may be instrumental in the initiation/exacerbation and/or maintenance of cellular leptin and insulin resistance (Figure 2b3). 59,91,207 In the case of SOCS3, increased expression is seen as early as 2 days in AgRP neurones and 2 weeks in POMC neurones.…”

Section: Insulin Resistance and Metabolic Diseasementioning

confidence: 99%

Insulin action in the brain: Roles in energy and glucose homeostasis

Dodd

Tiganis

2017

J Neuroendocrinology

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A growing body of evidence from research in rodents and humans has identified insulin as an important neuoregulatory peptide in the brain, where it coordinates diverse aspects of energy balance and peripheral glucose homeostasis. This review discusses where and how insulin interacts within the brain and evaluates the physiological and pathophysiological consequences of central insulin signalling in metabolism, obesity and type 2 diabetes. K E Y W O R D SAgRP, energy homeostasis, glucose homeostasis, hypothalamus, insulin, POMC | INTRODUCTIONInsulin targets peripheral tissues, including skeletal muscle, adipose tissue, where it promotes glucose uptake from the blood, and the liver, where it inhibits gluconeogenesis and glycogenolysis and promotes glycogen synthesis to coordinately repress hepatic glucose production.In this way, insulin prevents postprandial hyperglycaemia and maintains euglycaemia. In addition to these peripheral targets, insulin also signals in the brain, although the physiological significance of this interaction has only recently started to emerge. Research over the past two decades has provided compelling evidence that central insulin signalling plays pivotal roles in many aspects of energy and glucose homeostasis (Figure 1). Given the epidemics of obesity and type 2 diabetes (T2D) in developed and increasingly developing countries, there is a pressing need to fully understand the mechanisms by which the body coordinates energy and glucose homeostasis. A key hallmark of obesity and T2D is insulin resistance, where defective insulin signalling downstream of the insulin receptor (IR) renders the peripheral target tissues of insulin insensitive to the action of insulin. What is becoming increasingly apparent is that neurones in the brain also become resistant to insulin; however the relative contributions of central insulin resistance to the development of obesity and T2D remain poorly understood.This review discusses the role of insulin in the brain with respect to coordinating glucose metabolism with energy expenditure. In particular, we discuss our understanding of the locations and mechanisms by which insulin elicits its effects in the brain, its influence on glucose metabolism and energy expenditure, and the potential contributions of central insulin resistancein the development of obesity and the metabolic syndrome.

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Deficiency of PTP1B Attenuates Hypothalamic Inflammation via Activation of the JAK2-STAT3 Pathway in Microglia

Cited by 57 publications

References 53 publications

miR-135a Protects Dextran Sodium Sulfate-Induced Inflammation in Human Colorectal Cell Lines by Activating STAT3 Signal

miR-135a Protects Dextran Sodium Sulfate-Induced Inflammation in Human Colorectal Cell Lines by Activating STAT3 Signal

Infliximab ameliorates tumor necrosis factor‐alpha‐induced insulin resistance by attenuating PTP1B activation in 3T3L1 adipocytes in vitro

Insulin action in the brain: Roles in energy and glucose homeostasis

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