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

• Published in: EBioMedicine 2017-02, Vol.16 (C), p.172-183
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Diet, High-Fat - adverse effects; Enzyme Activation; Female; Gene Expression; High fat diet; Hypothalamic inflammation; Hypothalamus - metabolism; Hypothalamus - pathology; Inflammation - etiology; Inflammation - genetics; Inflammation - metabolism; Interleukin-10 - genetics; Interleukin-10 - metabolism; Janus Kinase 2 - metabolism; Male; Mice, Knockout; Microglia; Microglia - metabolism; Microscopy, Confocal; Obesity; Organ Culture Techniques; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - deficiency; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - genetics; Protein tyrosine phosphatase-1B; Research Paper; Reverse Transcriptase Polymerase Chain Reaction; Signal transducer and activator of transcription-3; Signal Transduction; STAT3 Transcription Factor - metabolism; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2017.01.007

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. •Hypothalamic inflammation induced by a high fat diet is decreased in PTP1B KO mice.•A high fat diet increases STAT3 phosphorylation in hypothalamic microglia in PTP1B KO mice.•STAT3 activation in microglia is responsible for the attenuation of hypothalamic inflammation in PTP1B KO mice. Diet-induced obesity is associated with inflammation not only in the peripheral tissues but also in the hypothalamus, and hypothalamic inflammation causes leptin resistance. Recent studies suggest that hypothalamic glial cells, including microglia, are involved in the inflammatory process in response to a high fat diet. Here we showed that PTP1B-deficiency enhanced JAK2-STAT3 signaling in hypothalamic microglia and attenuated inflammation. While it is well known that JAK2-STAT3 pathways in neurons mediate leptin signaling to regulate energy balance, this study revealed another important role of JAK2-STAT3 signaling in microglia, which attenuates hypothalamic inflammation. [Display omitted]