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    • Protein tyrosine phosphatase B PTP B is

    2018-11-14

    Protein tyrosine phosphatase 1B (PTP1B) is a non-receptor tyrosine phosphatase that is widely expressed in the body, and negatively regulates leptin signaling by dephosphorylating Janus Activating Kinase 2 (JAK2) in the hypothalamus (Tsou and Bence, 2012; Myers et al., 2001; Zhang et al., 2015). Animals under HFD conditions show increased PTP1B expression in the hypothalamus (Zabolotny et al., 2008), and that increase facilitates the storage of body fat (Picardi et al., 2008; White et al., 2009; Zabolotny et al., 2008). Moreover, PTP1B–deficiency in the whole body, Nintedanib or proopiomelanocortin (POMC) neurons leads to the increased phosphorylation of JAK2, and protects against obesity induced by a HFD (Klaman et al., 2000; Bence et al., 2006; Banno et al., 2010; Zabolotny et al., 2002; Cheng et al., 2002). PTP1B has also been implicated in the regulation of inflammatory responses in cells, including macrophages, myeloid cells and microglia (Zhang et al., 2013; Grant et al., 2014; Pike et al., 2014; Song et al., 2016). However, the role of PTP1B in hypothalamic inflammation induced by a HFD has yet to be clarified.
    Materials and Methods
    Results
    Discussion It is reported that a HFD reduces leptin-induced STAT3 phosphorylation in the arcuate nucleus of WT mice (Munzberg et al., 2004), and that leptin sensitivity in hypothalamic neurons was increased in PTP1B KO compared to WT mice, which makes KO mice resistant to diet-induced obesity (Zabolotny et al., 2002; Bence et al., 2006). In the present study, hypothalamic inflammation, which could be related to obesity and leptin resistance (De Git and Adan, 2015), was examined in mice at the age of 7weeks when there were no significant differences in body weight between the WT and KO mice fed a HFD. Thus, the comparison between genotypes in the present study has provided us with an opportunity to elucidate the underlying mechanisms by which body weight is increased in WT compared to KO mice on a HFD. Consistent with previous studies (De Souza et al., 2005; Valdearcos et al., 2014), our data showed that TNFα immunoreactivity was increased in the arcuate nucleus in WT mice maintained on a HFD, but this was not the case in PTP1B KO mice. The analyses of Tnf and Il10 mRNA expression levels further support the conclusion that inflammation in the hypothalamus was not activated in KO mice at the age of 7weeks. Thus, it is indicated that hypothalamic inflammation preceded the relative increases in body weight in WT compared to KO mice fed a HFD. On the other hand, our data also showed that there were no significant differences in the activation of signaling pathways such as p65, p38, JNK and ERK between genotypes. This is probably because these signal transducers downstream from the TNFα receptor are not substrates for PTP1B (Tsou and Bence, 2012). There are several lines of evidence that the JAK2-STAT3 signaling pathway functions downstream from the TNFα receptor (Romanatto et al., 2007; Guo et al., 1998; Miscia et al., 2002; Sica and Mantovani, 2012). The activated STAT3 is reported to constitute a dimer that translocates into the nucleus to exert anti-inflammatory effects by decreasing Tnf mRNA expression and increasing Il10 mRNA expression (Benkhart et al., 2000; Hutchins et al., 2012, 2013). Conversely, STAT3 deficiency in macrophages is reported to increase inflammation (Takeda et al., 1999; Yoo et al., 2002), and previous studies revealed that PTP1B deficiency in macrophages decreased TNFα expression and increased IL-10 expression via activation of the STAT3 pathway in the peripheral tissues (Zhang et al., 2013; Grant et al., 2014; Pike et al., 2014). In the present study, we confirmed the findings of previous studies that STAT3 phosphorylation in the hypothalamus was increased in WT mice on a HFD (Ottaway et al., 2015; Knight et al., 2010; Martin et al., 2006). Our data also demonstrated that STAT3 phosphorylation in microglia increases more in KO mice than in WT mice on a HFD. The increased STAT3 phosphorylation is accompanied by the attenuation of hypothalamic inflammation in vivo and in primary hypothalamic cultures, and the inhibition of STAT3 phosphorylation as well as depletion of microglia completely eliminated the differences between genotypes in the cultures. These data suggest that PTP1B–deficiency in microglia activates the JAK2-STAT3 signaling pathways that lead to the attenuation of hypothalamic inflammation. Our data thus revealed an important role of the JAK2-STAT3 signaling pathway in hypothalamic microglia, a pathway that prevents hypothalamic inflammation and possibly obesity by a HFD. On the other hand, our data also showed that in WT mice, in which STAT3 phosphorylation is relatively low compared to KO mice, the decreased STAT3 phosphorylation by STAT3 inhibitors did not affect the inflammatory responses to the TNFα treatment (Fig.5 c-h), suggesting that the anti-inflammatory action of the JAK2-STAT3 pathway manifests only after the phosphorylation reaches certain levels.