Faculty Profiles - ARIMA, Hiroshi

Magnetic-activated cell sorting法を用いた視床下部アストロサイトの単離と機能解析

メトトレキサート治療中に両側副腎腫大を来した一例

半田朋子, 森下啓明, 伊藤崇浩, 有馬寛

日本内分泌学会雑誌 Vol. 93 ( 2 ) page： 642 - 642 2017.10

杉山摩利子, 坂野僚一, 滝啓吾, 溝口暁, 恒川卓, 高木博, 伊藤禎浩, 小峯起, 山中宏二, 有馬寛

肥満研究 Vol. 23 ( Suppl. ) page： 212 - 212 2017.9

Randomized controlled trial for assessment of Internet of Things system to guide intensive glucose control in diabetes outpatients: Nagoya Health Navigator Study protocol International journal Open Access

Takeshi Onoue, Motomitsu Goto, Tomoko Kobayashi, Takashi Tominaga, Masahiko Ando, Hiroyuki Honda, Yasuko Yoshida, Takahiro Tosaki, Hisashi Yokoi, Sawako Kato, Shoichi Maruyama, Hiroshi Arima

NAGOYA JOURNAL OF MEDICAL SCIENCE Vol. 79 ( 3 ) page： 323 - 329 2017.8

Language：English Publishing type：Research paper (scientific journal) Publisher：NAGOYA UNIV, SCH MED

The Internet of Things (IoT) allows collecting vast amounts of health-relevant data such as daily activity, body weight (BW), and blood pressure (BP) automatically. The use of IoT devices to monitor diabetic patients has been studied, but could not evaluate IoT-dependent effects because health data were not measured in control groups. This multicenter, open-label, randomized, parallel group study will compare the impact of intensive health guidance using IoT and conventional medical guidance on glucose control. It will be conducted in outpatients with type 2 diabetes for a period of 6 months. IoT devices to measure amount of daily activity, BW, and BP will be provided to IoT group patients. Healthcare professionals (HCPs) will provide appropriate feedback according to the data. Non-IoT control, patients will be given measurement devices that do not have a feedback function. The primary outcome is glycated hemoglobin at 6 months. The study has already enrolled 101 patients, 50 in the IoT group and 51 in the non-IoT group, at the two participating outpatient clinics. The baseline characteristics of two groups did not differ, except for triglycerides. This will be the first randomized, controlled study to evaluate IoT-dependent effects of intensive feedback from HCPs. The results will validate a new method of health-data collection and provision of feedback suitable for diabetes support with increased effectiveness and low cost.

DOI： 10.18999/nagjms.79.3.323

Sequestosome 1 (SQSTMI/p62) maintains protein folding capacity under endoplasmic reticulum stress in mouse hypothalamic organotypic culture International journal

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

NEUROSCIENCE LETTERS Vol. 656 page： 103 - 107 2017.8

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Sequestosome 1 (SQSTM1) also known as ubiquitin-binding protein p62 (p62) is a cargo protein involved in the degradation of misfolded proteins via selective autophagy. Disruption of autophagy and resulting accumulation of misfolded proteins in the endoplasmic reticulum (ER) leads to ER stress. ER stress is implicated in several neurodegenerative diseases and obesity. As knockout of p62 (p62KO) reportedly induces obesity in mice, we examined how p62 contributes to ER stress and the ensuing unfolded protein response (UPR) in hypothalamus using mouse organotypic cultures in the present study. Cultures from p62KO mice showed significantly reduced formation of LC3-GFP puncta, an index of autophagosome formation, in response to the chemical ER stressor thapsigargin compared to wild-type (WT) cultures. Hypothalamic cultures from p62KO mice exhibited higher basal expression of the UPR/ER stress markers CHOP mRNA and ATF4 mRNA than WT cultures. Thapsigargin enhanced CHOP, ATF4, and BiP mRNA as well as p-elF2 alpha protein expression in both NWT and p62KO cultures, but all peak values were greater in p621(0 cultures. A proteasome inhibitor increased p62 expression in WT cultures and upregulated the UPR/ER stress markers CHOP mRNA and ATF4 mRNA in both genotypes, but to a greater extent in p62KO cultures. Therefore, p62 deficiency disturbed autophagosome formation and enhanced both basal and chemically induced ER stress, suggesting that p62 serves to prevent ER stress in mouse hypothalamus by maintaining protein folding capacity. (C) 2017 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.neulet.2017.06.014

PTP1B deficiency improves hypothalamic insulin sensitivity resulting in the attenuation of AgRP mRNA expression under high-fat diet conditions International journal Open Access

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

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Vol. 488 ( 1 ) page： 116 - 121 2017.6

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Hypothalamic insulin receptor signaling regulates energy balance and glucose homeostasis via agouti related protein (AgRP). While protein tyrosine phosphatase 1B (PTP1B) is classically known to be a negative regulator of peripheral insulin signaling by dephosphorylating both insulin receptor beta (IR beta) and insulin receptor substrate, the role of PTP1B in hypothalamic insulin signaling remains to be fully elucidated. In the present study, we investigated the role of PTP1B in hypothalamic insulin signaling using PTP1B deficient (KO) mice in vivo and ex vivo. For the in vivo study, hypothalamic insulin resistance induced by a high-fat diet (HFD) improved in KO mice compared to wild-type (WT) mice. Hypothalamic AgRP mRNA expression levels were also significantly decreased in KO mice independent of body weight changes. In an ex vivo study using hypothalamic organotypic cultures, insulin treatment significantly increased the phosphorylation of both IR beta and Akt in the hypothalamus of KO mice compared to WT mice, and also significantly decreased AgRP mRNA expression levels in KO mice. While incubation with inhibitors of phosphatidylinositol-3 kinase (PI3K) had no effect on basal levels of Akt phosphorylation, these suppressed insulin induction of Akt phosphorylation to almost basal levels in WT and KO mice. The inhibition of the PI3K-Akt pathway blocked the downregulation of AgRP mRNA expression in KO mice treated with insulin. These data suggest that PTP1B acts on the hypothalamic insulin signaling via the PI3K-Akt pathway. Together, our results suggest a deficiency of PTP1B improves hypothalamic insulin sensitivity resulting in the attenuation of AgRP mRNA expression under HFD conditions. (C) 2017 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2017.05.019

S100B impairs glycolysis via enhanced poly(ADP-ribosyl) ation of glyceraldehyde-3-phosphate dehydrogenase in rodent muscle cells International journal Open Access

Kaori Hosokawa, Yoji Hamada, Atsushi Fujiya, Masatoshi Murase, Ryuya Maekawa, Yasuhiro Niwa, Takako Izumoto, Yusuke Seino, Shin Tsunekawa, Hiroshi Arima

AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM Vol. 312 ( 6 ) page： E471 - E481 2017.6

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER PHYSIOLOGICAL SOC

S100 calcium-binding protein B (S100B), a multifunctional macromolecule mainly expressed in nerve tissues and adipocytes, has been suggested to contribute to the pathogenesis of obesity. To clarify the role of S100B in insulin action and glucose metabolism in peripheral tissues, we investigated the effect of S100B on glycolysis in myoblast and myotube cells. Rat myoblast L6 cells were treated with recombinant mouse S100B to examine glucose consumption, lactate production, glycogen accumulation, glycolytic metabolites and enzyme activity, insulin signaling, and poly(ADP-ribosyl)ation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Glycolytic metabolites were investigated by enzyme assays or metabolome analysis, and insulin signaling was assessed by Western blot analysis. Enzyme activity and poly(ADP-ribosyl) ation of GAPDH was evaluated by an enzyme assay and immunoprecipitation followed by dot blot with an anti-poly(ADP-ribose) antibody, respectively. S100B significantly decreased glucose consumption, glucose analog uptake, and lactate production in L6 cells, in either the presence or absence of insulin. In contrast, S100B had no effect on glycogen accumulation and insulin signaling. Metabolome analysis revealed that S100B increased the concentration of glycolytic intermediates upstream of GAPDH. S100B impaired GAPDH activity and increased poly(ADP-ribosyl) ated GAPDH proteins. The effects of S100B on glucose metabolism were mostly canceled by a poly(ADP-ribose) polymerase inhibitor. Similar results were obtained in C2C12 myotube cells. We conclude that S100B as a humoral factor may impair glycolysis in muscle cells independent of insulin action, and the effect may be attributed to the inhibition of GAPDH activity from enhanced poly(ADP-ribosyl) ation of the enzyme.

DOI： 10.1152/ajpendo.00328.2016

Anti-pituitary antibodies against corticotrophs in IgG4-related hypophysitis International journal

Naoko Iwata, Shintaro Iwama, Yoshihisa Sugimura, Yoshinori Yasuda, Kohtaro Nakashima, Seiji Takeuchi, Daisuke Hagiwara, Yoshihiro Ito, Hidetaka Suga, Motomitsu Goto, Ryoichi Banno, Patrizio Caturegli, Teruhiko Koike, Yoshiharu Oshida, Hiroshi Arima

PITUITARY Vol. 20 ( 3 ) page： 301 - 310 2017.6

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Purpose IgG4-related disease is a systemic inflammatory disease characterized by infiltration of IgG4-positive plasma cells into multiple organs, including the pituitary gland. Autoimmunity is thought to be involved in the pathogenesis of IgG4-related disease. The diagnosis of IgG4-related hypophysitis (IgG4-RH) is difficult because its clinical features, such as pituitary swelling and hypopituitarism, are similar to those of other pituitary diseases, including lymphocytic hypophysitis and sellar/suprasellar tumors. The presence and significance of anti-pituitary antibodies (APA) in IgG4-RH is unclear.
Methods In this case-control study, we used single indirect immunofluorescence on human pituitary substrates to assess the prevalence of serum APA in 17 patients with IgG4-RH, 8 control patients with other pituitary diseases (lymphocytic infundibulo-neurohypophysitis, 3; craniopharyngioma, 2; germinoma, 3), and 9 healthy subjects.We further analyzed the endocrine cells targeted by the antibodies using double indirect immunofluorescence.
Results APA were found in 5 of 17 patients with IgG4-RH (29%), and in none of the pituitary controls or healthy subjects. The endocrine cells targeted by the antibodies in the 5 IgG4-RH cases were exclusively corticotrophs. Antibodies were of the IgG1 subclass, rather than IgG4, in all 5 cases, suggesting that IgG4 is not directly involved in the pathogenesis. Finally, antibodies recognized pro-opiomelanocortin in 2 of the cases.
Conclusions Our study suggests that autoimmunity is involved in the pathogenesis of IgG4-RH and that corticotrophs are the main antigenic target, highlighting a possible new diagnostic marker for this condition.

DOI： 10.1007/s11102-016-0780-8

免疫チェックポイント阻害薬による内分泌障害(臨床研究第一報)

小林朋子, 岩間信太郎, 安田康紀, 岩田尚子, 椙村益久, 安藤雄一, 秋山真志, 長谷川好規, 有馬寛

日本内分泌学会雑誌 Vol. 93 ( Suppl.Update ) page： 70 - 72 2017.6

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：(一社)日本内分泌学会

2016年6月時点において、当院で免疫チェックポイント阻害薬として抗CTLA-4抗体イピリムマブ(Ipi)が投与された12例および抗PD-1抗体ニボルマブ(Niv)が投与された23例を対象に、内分泌学的評価を行った。その結果、Ipi投与中の内分泌有害事象は下垂体炎が2件(16.7%)、低Na血症が2件(16.7%)、副腎炎が1件(8.3%)、TSH値異常が4件(33.3%)に認められた。Niv投与中の内分泌有害事象はTSH値異常が7件(35.0%)、破壊性甲状腺炎が1件(4.3%)、甲状腺自己抗体陽転化が1件(4.3%)に認められた。Ipi投与中に発生した下垂体炎は、2件とも前治療としてNivが投与されており、Niv治療歴のある場合にはIpiによる下垂体炎を特に注意する必要があると考えられた。また、当院で経験した重篤な破壊性甲状腺炎の経過から、Niv投与前に甲状腺自己抗体が陽性の場合には甲状腺障害の発症に注意が必要であると示唆された。

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J01160&link_issn=&doc_id=20170718400022&doc_link_id=10.1507%2Fendocrine.93.S.Update_70&url=https%3A%2F%2Fdoi.org%2F10.1507%2Fendocrine.93.S.Update_70&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

4-PBAは家族性中枢性尿崩症モデルマウスにおいて多尿の進行およびバソプレシンニューロンの細胞死を抑制する

橡谷昌佳, 萩原大輔, 宮田崇, 森下啓明, 有馬寛

日本内分泌学会雑誌 Vol. 93 ( 1 ) page： 263 - 263 2017.4

抗ラブフィリン3A抗体の小児期発症リンパ球性漏斗下垂体後葉炎における診断的有用性に関する検討

岩田尚子, 岩間信太郎, 安田康紀, 椙村益久, 有馬寛

日本内分泌学会雑誌 Vol. 93 ( 1 ) page： 317 - 317 2017.4

ラブフィリン3A免疫マウスにおける視床下部下垂体後葉炎び病態の解析

安田康紀, 岩間信太郎, 岩田尚子, 椙村益久, 有馬寛

日本内分泌学会雑誌 Vol. 93 ( 1 ) page： 276 - 276 2017.4

ニボルマブによる甲状腺障害の臨床的特徴

小林朋子, 岩間信太郎, 安田康紀, 岩田尚子, 横田憲二, 椙村益久, 近藤征史, 安藤雄一, 秋山真志, 長谷川好規, 有馬寛

日本内分泌学会雑誌 Vol. 93 ( 1 ) page： 360 - 360 2017.4

AVPニューロンのin vitro実験系の確立 AVP-Venusマウスを用いた検討

萩原大輔, 宮田崇, 橡谷昌佳, 森下啓明, 有馬寛

日本内分泌学会雑誌 Vol. 93 ( 1 ) page： 276 - 276 2017.4

疾患特異的iPS細胞を用いた家族性中枢性尿崩症の病態解明

光本一樹, 須賀英隆, 山田登美子, 加納麻弓子, 橡谷昌佳, 大曽根親文, 笠井貴敏, 萩原大輔, 有馬寛

日本内分泌学会雑誌 Vol. 93 ( 1 ) page： 276 - 276 2017.4

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

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

EBIOMEDICINE Vol. 16 page： 172 - 183 2017.2

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

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 TNF alpha 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. (C) 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

DOI： 10.1016/j.ebiom.2017.01.007

Effects of clozapine on adipokine secretions/productions and lipid droplets in 3T3-L1 adipocytes. Open Access

Tomomi Tsubai, Akira Yoshimi, Yoji Hamada, Makoto Nakao, Hiroshi Arima, Yutaka Oiso, Yukihiro Noda

Journal of pharmacological sciences Vol. 133 ( 2 ) page： 79 - 87 2017.2

Language：English Publishing type：Research paper (scientific journal)

Clozapine, a second-generation antipsychotic (SGA), is a cause of side effects related to metabolic syndrome. The participation of serotonin 5-HT2C and histamine H1 receptors in the central nervous system has been reported as a mechanism of the weight gain caused by clozapine. In the present study, we investigated the direct pharmacological action of clozapine on the 3T3-L1 adipocytes and compared it to that of blonanserin, an SGA with low affinity for both receptors. Short-term exposure to clozapine decreased secretion and mRNA expression of leptin. Long-term exposure decreased leptin as well as adiponectin secretion, and further increased lipid droplets accumulation. However, short- and long-term exposures to blonanserin did not affect these parameters. A selective serotonin 5-HT2C, but not a histamine H1, receptor antagonist enhanced the decreased secretion of leptin induced by short-term exposure to clozapine, but did not affect the increased accumulation of lipid droplets. Our findings indicate that clozapine, but not blonanserin, strongly and directly affected the secretion of adipokines, such as leptin, in adipocytes and caused adipocyte enlargement.

DOI： 10.1016/j.jphs.2017.01.004