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

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

Research output: Contribution to journalArticle

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Abstract

Protein tyrosine phosphatase 1B (PTP1B) regulates leptin signaling in hypothalamic neurons via the JAK2-STAT3 pathway. PTP1B has also been implicated in the regulation of inflammation in the periphery. However, the role of PTP1B in hypothalamic inflammation, which is induced by a high-fat diet (HFD), remains to be elucidated. Here, we showed that STAT3 phosphorylation (p-STAT3) was increased in microglia in the hypothalamic arcuate nucleus of PTP1B knock-out mice (KO) on a HFD, accompanied by decreased Tnf and increased Il10 mRNA expression in the hypothalamus compared to wild-type mice (WT). In hypothalamic organotypic cultures, incubation with TNFα led to increased p-STAT3, accompanied by decreased Tnf and increased Il10 mRNA expression, in KO compared to WT. Incubation with p-STAT3 inhibitors or microglial depletion eliminated the differences in inflammation between genotypes. These data indicate an important role of JAK2-STAT3 signaling negatively regulated by PTP1B in microglia, which attenuates hypothalamic inflammation under HFD conditions.

Original languageEnglish
Pages (from-to)172-183
Number of pages12
JournalEBioMedicine
Volume16
DOIs
Publication statusPublished - 01-02-2017

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Non-Receptor Type 1 Protein Tyrosine Phosphatase
Microglia
Chemical activation
Inflammation
High Fat Diet
Nutrition
Fats
Knockout Mice
Interleukin-10
Messenger RNA
Arcuate Nucleus of Hypothalamus
Phosphorylation
Leptin
Hypothalamus
Neurons
Genotype

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Tsunekawa, T., Banno, R., Mizoguchi, A., Sugiyama, M., Tominaga, T., Onoue, T., ... Arima, H. (2017). Deficiency of PTP1B Attenuates Hypothalamic Inflammation via Activation of the JAK2-STAT3 Pathway in Microglia. EBioMedicine, 16, 172-183. https://doi.org/10.1016/j.ebiom.2017.01.007
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. / Deficiency of PTP1B Attenuates Hypothalamic Inflammation via Activation of the JAK2-STAT3 Pathway in Microglia. In: EBioMedicine. 2017 ; Vol. 16. pp. 172-183.
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abstract = "Protein tyrosine phosphatase 1B (PTP1B) regulates leptin signaling in hypothalamic neurons via the JAK2-STAT3 pathway. PTP1B has also been implicated in the regulation of inflammation in the periphery. However, the role of PTP1B in hypothalamic inflammation, which is induced by a high-fat diet (HFD), remains to be elucidated. Here, we showed that STAT3 phosphorylation (p-STAT3) was increased in microglia in the hypothalamic arcuate nucleus of PTP1B knock-out mice (KO) on a HFD, accompanied by decreased Tnf and increased Il10 mRNA expression in the hypothalamus compared to wild-type mice (WT). In hypothalamic organotypic cultures, incubation with TNFα led to increased p-STAT3, accompanied by decreased Tnf and increased Il10 mRNA expression, in KO compared to WT. Incubation with p-STAT3 inhibitors or microglial depletion eliminated the differences in inflammation between genotypes. These data indicate an important role of JAK2-STAT3 signaling negatively regulated by PTP1B in microglia, which attenuates hypothalamic inflammation under HFD conditions.",
author = "Taku Tsunekawa and Ryoichi Banno and Akira Mizoguchi and Mariko Sugiyama and Takashi Tominaga and Takeshi Onoue and Daisuke Hagiwara and Yoshihiro Ito and Shintaro Iwama and Motomitsu Goto and Hidetaka Suga and Yoshihisa Sugimura and Hiroshi Arima",
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Tsunekawa, T, Banno, R, Mizoguchi, A, Sugiyama, M, Tominaga, T, Onoue, T, Hagiwara, D, Ito, Y, Iwama, S, Goto, M, Suga, H, Sugimura, Y & Arima, H 2017, 'Deficiency of PTP1B Attenuates Hypothalamic Inflammation via Activation of the JAK2-STAT3 Pathway in Microglia', EBioMedicine, vol. 16, pp. 172-183. https://doi.org/10.1016/j.ebiom.2017.01.007

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.

In: EBioMedicine, Vol. 16, 01.02.2017, p. 172-183.

Research output: Contribution to journalArticle

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T1 - Deficiency of PTP1B Attenuates Hypothalamic Inflammation via Activation of the JAK2-STAT3 Pathway in Microglia

AU - Tsunekawa, Taku

AU - Banno, Ryoichi

AU - Mizoguchi, Akira

AU - Sugiyama, Mariko

AU - Tominaga, Takashi

AU - Onoue, Takeshi

AU - Hagiwara, Daisuke

AU - Ito, Yoshihiro

AU - Iwama, Shintaro

AU - Goto, Motomitsu

AU - Suga, Hidetaka

AU - Sugimura, Yoshihisa

AU - Arima, Hiroshi

PY - 2017/2/1

Y1 - 2017/2/1

N2 - Protein tyrosine phosphatase 1B (PTP1B) regulates leptin signaling in hypothalamic neurons via the JAK2-STAT3 pathway. PTP1B has also been implicated in the regulation of inflammation in the periphery. However, the role of PTP1B in hypothalamic inflammation, which is induced by a high-fat diet (HFD), remains to be elucidated. Here, we showed that STAT3 phosphorylation (p-STAT3) was increased in microglia in the hypothalamic arcuate nucleus of PTP1B knock-out mice (KO) on a HFD, accompanied by decreased Tnf and increased Il10 mRNA expression in the hypothalamus compared to wild-type mice (WT). In hypothalamic organotypic cultures, incubation with TNFα led to increased p-STAT3, accompanied by decreased Tnf and increased Il10 mRNA expression, in KO compared to WT. Incubation with p-STAT3 inhibitors or microglial depletion eliminated the differences in inflammation between genotypes. These data indicate an important role of JAK2-STAT3 signaling negatively regulated by PTP1B in microglia, which attenuates hypothalamic inflammation under HFD conditions.

AB - Protein tyrosine phosphatase 1B (PTP1B) regulates leptin signaling in hypothalamic neurons via the JAK2-STAT3 pathway. PTP1B has also been implicated in the regulation of inflammation in the periphery. However, the role of PTP1B in hypothalamic inflammation, which is induced by a high-fat diet (HFD), remains to be elucidated. Here, we showed that STAT3 phosphorylation (p-STAT3) was increased in microglia in the hypothalamic arcuate nucleus of PTP1B knock-out mice (KO) on a HFD, accompanied by decreased Tnf and increased Il10 mRNA expression in the hypothalamus compared to wild-type mice (WT). In hypothalamic organotypic cultures, incubation with TNFα led to increased p-STAT3, accompanied by decreased Tnf and increased Il10 mRNA expression, in KO compared to WT. Incubation with p-STAT3 inhibitors or microglial depletion eliminated the differences in inflammation between genotypes. These data indicate an important role of JAK2-STAT3 signaling negatively regulated by PTP1B in microglia, which attenuates hypothalamic inflammation under HFD conditions.

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