2022/04/11 更新

写真a

スギヤマ マリコ
杉山 摩利子
SUGIYAMA Mariko
所属
医学部附属病院 糖尿病・内分泌内科 助教
大学院担当
大学院医学系研究科
職名
助教
外部リンク

学位 1

  1. 博士(医学) ( 2018年3月   名古屋大学 ) 

研究キーワード 3

  1. 肥満

  2. 糖尿病

  3. 内分泌

研究分野 1

  1. ライフサイエンス / 代謝、内分泌学

学歴 2

  1. 名古屋大学   医学系研究科   糖尿病・内分泌内科学

    - 2018年3月

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    国名: 日本国

  2. 名古屋大学   医学部   医学科

    - 2009年3月

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    国名: 日本国

所属学協会 5

  1. 日本内科学会

  2. 日本糖尿病学会

  3. 日本内分泌学会

  4. 日本甲状腺学会

  5. 日本肥満学会

 

論文 31

  1. GABA(B) Receptor Signaling in the Mesolimbic System Suppresses Binge-like Consumption of a High-Fat Diet 国際誌

    Tsunekawa Taku, Banno Ryoichi, Yaginuma Hiroshi, Taki Keigo, Mizoguchi Akira, Sugiyama Mariko, Onoue Takeshi, Takagi Hiroshi, Hagiwara Daisuke, Ito Yoshihiro, Iwama Shintaro, Goto Motomitsu, Suga Hidetaka, Bettler Bernhard, Arima Hiroshi

    ISCIENCE   20 巻   頁: 337 - +   2019年10月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:iScience  

    Binge eating could contribute to the development of obesity, and previous studies suggest that gamma-aminobutyric acid (GABA) type B receptor (GABABR) signaling is involved in the regulation of binge eating. Here, we show that time-restricted access to a high-fat diet (HFD) induces binge-like eating behavior in wild-type mice. HFD consumption during restricted time was significantly increased in corticostriatal neuron-specific GABABR-deficient mice compared with wild-type mice. Furthermore, the GABABR agonist baclofen suppressed HFD intake during restricted time in wild-type mice but not in corticostriatal or dopaminergic neuron-specific GABABR-deficient mice. In contrast, there were no significant differences in food consumption among genotypes under ad libitum access to HFD. Thus, our data show that the mesolimbic system regulates food consumption under time-restricted but not ad libitum access to HFD and have identified a mechanism by which GABABR signaling suppresses binge-like eating of HFD.

    DOI: 10.1016/j.isci.2019.09.032

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  2. PTP1B deficiency improves hypothalamic insulin sensitivity resulting in the attenuation of AgRP mRNA expression under high-fat diet conditions 国際誌

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

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   488 巻 ( 1 ) 頁: 116 - 121   2017年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Biochemical and Biophysical Research Communications  

    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 β (IRβ) 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 IRβ 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.

    DOI: 10.1016/j.bbrc.2017.05.019

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  3. Deficiency of PTP1B Attenuates Hypothalamic Inflammation via Activation of the JAK2-STAT3 Pathway in Microglia 国際誌

    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

    EBIOMEDICINE   16 巻   頁: 172 - 183   2017年2月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:EBioMedicine  

    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.

    DOI: 10.1016/j.ebiom.2017.01.007

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  4. Hypothalamic Contribution to Pituitary Functions Is Recapitulated In Vitro Using 3D-Cultured Human iPS Cells 国際誌

    Kasai Takatoshi, Suga Hidetaka, Sakakibara Mayu, Ozone Chikafumi, Matsumoto Ryusaku, Kano Mayuko, Mitsumoto Kazuki, Ogawa Koichiro, Kodani Yu, Nagasaki Hiroshi, Inoshita Naoko, Sugiyama Mariko, Onoue Takeshi, Tsunekawa Taku, Ito Yoshihiro, Takagi Hiroshi, Hagiwara Daisuke, Iwama Shintaro, Goto Motomitsu, Banno Ryoichi, Takahashi Jun, Arima Hiroshi

    CELL REPORTS   30 巻 ( 1 ) 頁: 18 - +   2020年1月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cell Reports  

    The pituitary is a major hormone center that secretes systemic hormones responding to hypothalamus-derived-releasing hormones. Previously, we reported the independent pituitary induction and hypothalamic differentiation of human embryonic stem cells (ESCs). Here, a functional hypothalamic-pituitary unit is generated using human induced pluripotent stem (iPS) cells in vitro. The adrenocorticotropic hormone (ACTH) secretion capacity of the induced pituitary reached a comparable level to that of adult mouse pituitary because of the simultaneous maturation with hypothalamic neurons within the same aggregates. Corticotropin-releasing hormone (CRH) from the hypothalamic area regulates ACTH cells similarly to our hypothalamic-pituitary axis. Our induced hypothalamic-pituitary units respond to environmental hypoglycemic condition in vitro, which mimics a life-threatening situation in vivo, through the CRH-ACTH pathway, and succeed in increasing ACTH secretion. Thus, we generated powerful hybrid organoids by recapitulating hypothalamic-pituitary development, showing autonomous maturation on the basis of interactions between developing tissues.

    DOI: 10.1016/j.celrep.2019.12.009

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  5. Dipeptidyl peptidase-4 inhibitor anagliptin reduces fasting apolipoprotein B-48 levels in patients with type 2 diabetes: A randomized controlled 国際誌

    Onoue Takeshi, Goto Motomitsu, Wada Eri, Furukawa Mariko, Okuji Takayuki, Okada Norio, Kobayashi Tomoko, Iwama Shintaro, Sugiyama Mariko, Tsunekawa Taku, Takagi Hiroshi, Hagiwara Daisuke, Ito Yoshihiro, Morishita Yoshiaki, Seino Yusuke, Suga Hidetaka, Banno Ryoichi, Hamada Yoji, Ando Masahiko, Yamamori Etsuko, Arima Hiroshi

    PLOS ONE   15 巻 ( 1 ) 頁: e0228004   2020年1月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PLoS ONE  

    Type 2 diabetes and dyslipidemia are diseases that collectively increase the risk of patients developing cardiovascular complications. Several incretin-based drugs are reported to improve lipid metabolism, and one of these medications, anagliptin, is a dipeptidyl peptidase- 4 (DPP-4) inhibitor that has been shown to decrease serum triglyceride and low-density lipoproteins cholesterol. This study aimed to conduct an investigation into the effects of anagliptin on serum lipid profiles. This multicenter, open-label, randomized (1:1), parallel group study was designed to evaluate the effects of anagliptin on serum lipid profiles (triglycerides, lipoproteins, apolipoproteins, and cholesterol fractions). The study involved 24 patients with type 2 diabetes at two participating hospitals for a period of 24 weeks. Patients were randomly assigned to the anagliptin (n = 12) or control (n = 12) groups. Patients in the anagliptin group were treated with 200 mg of the drug twice daily. Patients in the control group did not receive anagliptin, but continued with their previous treatment schedules. Lipid metabolism was examined under fasting conditions at baseline and 24 weeks. Patients treated with anagliptin for 24 weeks exhibited significantly reduced levels of serum apolipoprotein B-48, a marker for lipid transport from the intestine, compared with the control group patients (P < 0.05). After 24 weeks of treatment, serum adiponectin levels were significantly raised, whereas glycated hemoglobin (HbA1c) levels were significantly lower compared with the baseline in the anagliptin group (P < 0.05), but not in the control group. This study showed that the DPP-4 inhibitor anagliptin reduces fasting apolipoprotein B-48 levels, suggesting that this drug may have beneficial effects on lipid metabolism possibly mediated by the inhibition of intestinal lipid transport.

    DOI: 10.1371/journal.pone.0228004

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  6. Diagnosis of central diabetes insipidus using a vasopressin radioimmunoassay during hypertonic saline infusion

    Takagi Hiroshi, Hagiwara Daisuke, Handa Tomoko, Sugiyama Mariko, Onoue Takeshi, Tsunekawa Taku, Ito Yoshihiro, Iwama Shintaro, Goto Motomitsu, Suga Hidetaka, Banno Ryoichi, Takahashi Kunihiko, Matsui Shigeyuki, Arima Hiroshi

    ENDOCRINE JOURNAL   67 巻 ( 3 ) 頁: 267 - 274   2020年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Endocrine Journal  

    Central diabetes insipidus (CDI) is characterized by polyuria and polydipsia caused by impairment of arginine vasopressin (AVP) secretion. In this study, we evaluated plasma AVP concentrations during a hypertonic saline infusion test using a new AVP radioimmunoassay (RIA) which is now available in Japan. Thirteen control subjects, mostly with hypothalamo-pituitary disease but without CDI, and 13 patients with CDI were enrolled in the study. Whether or not subjects had CDI was determined based on the totality of clinical data, which included urine volumes and osmolality. Regression analysis of plasma AVP and serum Na concentrations revealed that the gradient was significantly lower in the CDI group than in the control group. The area under the receiver-operating-characteristic (ROC) curve was 0.99, and the <0.1 gradient cut-off values for the simple regression line to distinguish CDI from control had a 100% sensitivity and a 77% specificity. The ROC analysis with estimated plasma AVP concentrations at a serum Na concentration of 149 mEq/L showed that the area under the ROC curve was 1.0 and the <1.0 pg/mL cut-off values of plasma AVP had a 99% sensitivity and a 95% specificity. We conclude that measurement of AVP by RIA during a hypertonic saline infusion test can differentiate patients with CDI from those without CDI with a high degree of accuracy. Further investigation is required to confirm whether the cut-off values shown in this study are also applicable to a diagnosis of partial CDI or a differential diagnosis between CDI and primary polydipsia.

    DOI: 10.1507/endocrj.EJ19-0224

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  7. Improved methods for the differentiation of hypothalamic vasopressin neurons using mouse induced pluripotent stem cells 国際誌

    Mitsumoto Kazuki, Suga Hidetaka, Sakakibara Mayu, Soen Mika, Yamada Tomiko, Ozaki Hajime, Nagai Takashi, Kano Mayuko, Kasai Takatoshi, Ozone Chikafumi, Ogawa Koichiro, Sugiyama Mariko, Onoue Takeshi, Tsunekawa Taku, Takagi Hiroshi, Hagiwara Daisuke, Ito Yoshihiro, Iwama Shintaro, Goto Motomitsu, Banno Ryoichi, Arima Hiroshi

    STEM CELL RESEARCH   40 巻   頁: 101572 - 101572   2019年10月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Stem Cell Research  

    High differentiation efficiency is one of the most important factors in developing an in vitro model from pluripotent stem cells. In this report, we improved the handling technique applied to mouse-induced pluripotent stem (iPS) cells, resulting in better differentiation into hypothalamic vasopressin (AVP) neurons. We modified the culture procedure to make the maintenance of iPS cells in an undifferentiated state much easier. Three-dimensional floating culture was demonstrated to be effective for mouse iPS cells. We also improved the differentiation method with regards to embryology, resulting in a greater number of bigger colonies of AVP neurons differentiating from mouse iPS cells. Fgf8, which was not used in the original differentiation method, increased iPS differentiation into AVP neurons. These refinements will be useful as a valuable tool for the modeling of degenerative disease in AVP neurons in vitro using disease-specific iPS cells in future studies.

    DOI: 10.1016/j.scr.2019.101572

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  8. Tanycyte-Like Cells Derived From Mouse Embryonic Stem Culture Show Hypothalamic Neural Stem/Progenitor Cell Functions 国際誌

    Kano Mayuko, Suga Hidetaka, Ishihara Takeshi, Sakakibara Mayu, Soen Mika, Yamada Tomiko, Ozaki Hajime, Mitsumoto Kazuki, Kasai Takatoshi, Sugiyama Mariko, Onoue Takeshi, Tsunekawa Taku, Takagi Hiroshi, Hagiwara Daisuke, Ito Yoshihiro, Iwama Shintaro, Goto Motomitsu, Banno Ryoichi, Arima Hiroshi

    ENDOCRINOLOGY   160 巻 ( 7 ) 頁: 1701 - 1718   2019年7月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Endocrinology  

    Tanycytes have recently been accepted as neural stem/progenitor cells in the postnatal hypothalamus. Persistent retina and anterior neural fold homeobox (Rax) expression is characteristic of tanycytes in contrast to its transient expression of whole hypothalamic precursors. In this study, we found that Rax+ residual cells in the maturation phase of hypothalamic differentiation in mouse embryonic stem cell (mESC) cultures had similar characteristics to ventral tanycytes. They expressed typical neural stem/progenitor cell markers, including Sox2, vimentin, and nestin, and differentiated into mature neurons and glial cells. Quantitative RT-PCR analysis showed that Rax+ residual cells expressed Fgf-10, Fgf-18, and Lhx2, which are expressed by ventral tanycytes. They highly expressed tanycyte-specific genes Dio2 and Gpr50 compared with Rax+ early hypothalamic progenitor cells. Therefore, Rax+ residual cells in the maturation phase of hypothalamic differentiation were considered to be more differentiated and similar to late progenitor cells and tanycytes. They self-renewed and formed neurospheres when cultured with exogenous FGF-2. Additionally, these Rax+ neurospheres differentiated into three neuronal lineages (neurons, astrocytes, and oligodendrocytes), including neuropeptide Y+ neuron, that are reported to be differentiated from ventral tanycytes toward the arcuate nuclei. Thus, Rax+ residual cells were multipotent neural stem/progenitor cells. Rax+ neurospheres were stably passaged and retained high Sox2 expression even after multiple passages. These results suggest the successful induction of Rax+ tanycyte-like cells from mESCs [induced tanycyte-like (iTan) cells]. These hypothalamic neural stem/progenitor cells may have potential in regenerative medicine and as a research tool.

    DOI: 10.1210/en.2019-00105

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  9. Sequestosome 1 (SQSTMI/p62) maintains protein folding capacity under endoplasmic reticulum stress in mouse hypothalamic organotypic culture 国際誌

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

    NEUROSCIENCE LETTERS   656 巻   頁: 103 - 107   2017年8月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Neuroscience Letters  

    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-eIF2α protein expression in both WT and p62KO cultures, but all peak values were greater in p62KO 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.

    DOI: 10.1016/j.neulet.2017.06.014

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  10. Increased Risk of Thyroid Dysfunction by PD-1 and CTLA-4 Blockade in Patients Without Thyroid Autoantibodies at Baseline

    Iwama Shintaro, Kobayashi Tomoko, Yasuda Yoshinori, Okuji Takayuki, Ito Masaaki, Ando Masahiko, Zhou Xin, Yamagami Ayana, Onoue Takeshi, Kawaguchi Yohei, Miyata Takashi, Sugiyama Mariko, Takagi Hiroshi, Hagiwara Daisuke, Suga Hidetaka, Banno Ryoichi, Hase Tetsunari, Morise Masahiro, Wakahara Keiko, Yokota Kenji, Kato Masashi, Nishio Naoki, Tanaka Chie, Miyata Kazushi, Ogura Atsushi, Ito Takanori, Sawada Tsunaki, Shimokata Tomoya, Niimi Kaoru, Ohka Fumiharu, Ishigami Masatoshi, Gotoh Momokazu, Hashimoto Naozumi, Saito Ryuta, Kiyoi Hitoshi, Kajiyama Hiroaki, Ando Yuichi, Hibi Hideharu, Sone Michihiko, Akiyama Masashi, Kodera Yasuhiro, Arima Hiroshi

    JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM   107 巻 ( 4 ) 頁: E1620 - E1630   2022年3月

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    記述言語:日本語  

    DOI: 10.1210/clinem/dgab829

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  11. Functional Lactotrophs in Induced Adenohypophysis Differentiated From Human iPS Cells

    Miyake Natsuki, Nagai Takashi, Suga Hidetaka, Osuka Satoko, Kasai Takatoshi, Sakakibara Mayu, Soen Mika, Ozaki Hajime, Miwata Tsutomu, Asano Tomoyoshi, Kano Mayuko, Muraoka Ayako, Nakanishi Natsuki, Nakamura Tomoko, Goto Maki, Yasuda Yoshinori, Kawaguchi Yohei, Miyata Takashi, Kobayashi Tomoko, Sugiyama Mariko, Onoue Takeshi, Hagiwara Daisuke, Iwama Shintaro, Iwase Akira, Inoshita Naoko, Arima Hiroshi, Kajiyama Hiroaki

    ENDOCRINOLOGY   163 巻 ( 3 )   2022年3月

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    記述言語:日本語   出版者・発行元:Endocrinology (United States)  

    Prolactin (PRL), a hormone involved in lactation, is mainly produced and secreted by the lactotrophs of the anterior pituitary (AP) gland. We previously reported a method to generate functional adrenocorticotropic hormone-producing cells by differentiating the AP and hypothalamus simultaneously from human induced pluripotent stem cells (iPSCs). However, PRL-producing cells in the induced AP have not been investigated. Here, we confirmed the presence of PRL-producing cells and evaluated their endocrine functions. We differentiated pituitary cells from human iPSCs using serum-free floating culture of embryoid-like aggregates with quick reaggregation (SFEB-q) method and evaluated the appearance and function of PRL-producing cells. Secretion of PRL from the differentiated aggregates was confirmed, which increased with further culture. Fluorescence immunostaining and immunoelectron microscopy revealed PRL-producing cells and PRL-positive secretory granules, respectively. PRL secretion was promoted by various prolactin secretagogues such as thyrotropin-releasing hormone, vasoactive intestinal peptide, and prolactin-releasing peptide, and inhibited by bromocriptine. Moreover, the presence of tyrosine hydroxylase-positive dopaminergic nerves in the hypothalamic tissue area around the center of the aggregates connecting to PRL-producing cells indicated the possibility of recapitulating PRL regulatory mechanisms through the hypothalamus. In conclusion, we generated pituitary lactotrophs from human iPSCs; these displayed similar secretory responsiveness as human pituitary cells in vivo. In the future, this is expected to be used as a model of human PRL-producing cells for various studies, such as drug discovery, prediction of side effects, and elucidation of tumorigenic mechanisms using disease-specific iPSCs. Furthermore, it may help to develop regenerative medicine for the pituitary gland.

    DOI: 10.1210/endocr/bqac004

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  12. Predicting non-insulin-dependent state in patients with slowly progressive insulin-dependent (type 1) diabetes mellitus or latent autoimmune diabetes in adults. Reply to Sugiyama K and Saisho Y [letter]

    Wada Eri, Onoue Takeshi, Kinoshita Tamaki, Hayase Ayaka, Handa Tomoko, Ito Masaaki, Furukawa Mariko, Okuji Takayuki, Kobayashi Tomoko, Iwama Shintaro, Sugiyama Mariko, Takagi Hiroshi, Hagiwara Daisuke, Suga Hidetaka, Banno Ryoichi, Goto Motomitsu, Arima Hiroshi

    DIABETOLOGIA   65 巻 ( 1 ) 頁: 252 - 253   2022年1月

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    記述言語:日本語   出版者・発行元:Diabetologia  

    DOI: 10.1007/s00125-021-05610-4

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  13. Adult-onset autoimmune diabetes identified by glutamic acid decarboxylase autoantibodies: a retrospective cohort study

    Wada Eri, Onoue Takeshi, Kinoshita Tamaki, Hayase Ayaka, Handa Tomoko, Ito Masaaki, Furukawa Mariko, Okuji Takayuki, Kobayashi Tomoko, Iwama Shintaro, Sugiyama Mariko, Takagi Hiroshi, Hagiwara Daisuke, Suga Hidetaka, Banno Ryoichi, Goto Motomitsu, Arima Hiroshi

    DIABETOLOGIA   64 巻 ( 10 ) 頁: 2183 - 2192   2021年10月

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    記述言語:日本語   出版者・発行元:Diabetologia  

    Aims/hypothesis: Patients with GAD antibodies (GADAb) showing clinical features of type 2 diabetes typically exhibit progression to an insulin-dependent state in several months or years. This condition is diagnosed as slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) or latent autoimmune diabetes in adults, a subtype of adult-onset autoimmune diabetes. However, some patients diagnosed with adult-onset autoimmune diabetes do not progress to an insulin-dependent state. We conducted a retrospective cohort study to identify patients with non-insulin-dependent diabetes among those diagnosed with adult-onset autoimmune diabetes using measurable indicators in routine clinical practice. Methods: We surveyed data from the electronic medical records of all patients with GADAb from eight medical centres in Japan for selecting and analysing patients who matched the diagnostic criteria of SPIDDM. Results: Overall, 345 patients were analysed; of these, 162 initiated insulin therapy (insulin therapy group), whereas 183 did not (non-insulin therapy group) during the follow-up period (median 3.0 years). Patients in the non-insulin therapy group were more likely to be male and presented a later diabetes onset, shorter duration of diabetes, higher BMI, higher blood pressure levels, lower HbA1c levels, lower GADAb levels and lesser antidiabetic agent use than those in the insulin therapy group when GADAb was first identified as positive. A Cox proportional hazards model showed that BMI, HbA1c levels and GADAb levels were independent factors for progression to insulin therapy. Kaplan–Meier analyses revealed that 86.0% of the patients with diabetes having GADAb who presented all three factors (BMI ≥ 22 kg/m2, HbA1c < 75 mmol/mol [9.0%] and GADAb <10.0 U/ml) did not require insulin therapy for 4 years. Conclusions/interpretation: Higher BMI (≥22 kg/m2), lower HbA1c (<75 mmol/mol [9.0%]) and lower GADAb levels (<10.0 U/ml) can predict a non-insulin-dependent state for at least several years in Japanese patients with diabetes having GADAb. Graphical abstract: [Figure not available: see fulltext.]

    DOI: 10.1007/s00125-021-05516-1

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  14. GABA(B) receptor signaling in the caudate putamen is involved in binge-like consumption during a high fat diet in mice

    Sun Runan, Tsunekawa Taku, Hirose Tomonori, Yaginuma Hiroshi, Taki Keigo, Mizoguchi Akira, Miyata Takashi, Kobayashi Tomoko, Sugiyama Mariko, Onoue Takeshi, Takagi Hiroshi, Hagiwara Daisuke, Ito Yoshihiro, Iwama Shintaro, Suga Hidetaka, Banno Ryoichi, Bettler Bernhard, Arima Hiroshi

    SCIENTIFIC REPORTS   11 巻 ( 1 ) 頁: 19296   2021年9月

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    記述言語:日本語   出版者・発行元:Scientific Reports  

    Previous studies suggest that signaling by the gamma-aminobutyric acid (GABA) type B receptor (GABABR) is involved in the regulation of binge eating, a disorder which might contribute to the development of obesity. Here, we show that intermittent access to a high fat diet (HFD) induced binge-like eating behavior with activation of dopamine receptor d1 (drd1)-expressing neurons in the caudate putamen (CPu) and nucleus accumbens (NAc) in wild-type (WT) mice. The activation of drd1-expressing neurons during binge-like eating was substantially increased in the CPu, but not in the NAc, in corticostriatal neuron-specific GABABR-deficient knockout (KO) mice compared to WT mice. Treatment with the GABABR agonist, baclofen, suppressed binge-like eating behavior in WT mice, but not in KO mice, as reported previously. Baclofen also suppressed the activation of drd1-expressing neurons in the CPu, but not in the NAc, during binge-like eating in WT mice. Thus, our data suggest that GABABR signaling in CPu neurons expressing drd1 suppresses binge-like consumption during a HFD in mice.

    DOI: 10.1038/s41598-021-98590-9

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  15. Deficiency of WFS1 leads to the impairment of AVP secretion under dehydration in male mice 国際誌

    Kurimoto Junki, Takagi Hiroshi, Miyata Takashi, Hodai Yuichi, Kawaguchi Yohei, Hagiwara Daisuke, Suga Hidetaka, Kobayashi Tomoko, Sugiyama Mariko, Onoue Takeshi, Ito Yoshihiro, Iwama Shintaro, Banno Ryoichi, Tanabe Katsuya, Tanizawa Yukio, Arima Hiroshi

    PITUITARY   24 巻 ( 4 ) 頁: 582 - 588   2021年8月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Pituitary  

    Wolfram syndrome (WS) is mainly caused by mutations in the WFS1 gene and characterized by diabetes mellitus, optic atrophy, hearing loss, and central diabetes insipidus (CDI). WFS1 is an endoplasmic reticulum (ER)-resident transmembrane protein, and Wfs1 knockout (Wfs1−/−) mice, which have been used as a mouse model for WS, reportedly manifested impairment of glucose tolerance due to pancreatic β-cell loss. In the present study, we examined water balance, arginine vasopressin (AVP) secretion, and ER stress in AVP neurons of the hypothalamus in Wfs1−/− mice. There were no differences in urine volumes between Wfs1−/− and wild-type mice with free access to water. Conversely, when mice were subjected to intermittent water deprivation (WD) for 20 weeks, during which water was unavailable for 2 days a week, urine volumes were larger in Wfs1−/− mice, accompanied by lower urine AVP concentrations and urine osmolality, compared to wild-type mice. The mRNA expression of immunoglobulin heavy chain binding protein, a marker of ER stress, was significantly increased in the supraoptic nucleus and paraventricular nuclei in Wfs1−/− mice compared to wild-type mice after WD. Our results thus showed that Wfs1 knockout leads to a decrease in AVP secretion during dehydration, which could explain in part the mechanisms by which Wfs1 mutations cause CDI in humans.

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  16. Glucocorticoid receptor signaling in ventral tegmental area neurons increases the rewarding value of a high-fat diet in mice

    Mizoguchi Akira, Banno Ryoichi, Sun Runan, Yaginuma Hiroshi, Taki Keigo, Kobayashi Tomoko, Sugiyama Mariko, Tsunekawa Taku, Onoue Takeshi, Takagi Hiroshi, Hagiwara Daisuke, Ito Yoshihiro, Iwama Shintaro, Suga Hidetaka, Nagai Taku, Yamada Kiyofumi, Arima Hiroshi

    SCIENTIFIC REPORTS   11 巻 ( 1 ) 頁: 12873   2021年6月

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    記述言語:日本語   出版者・発行元:Scientific Reports  

    The reward system, which consists of dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens and caudate-putamen in the striatum, has an important role in the pathogenesis of not only drug addiction but also diet-induced obesity. In the present study, we examined whether signaling through glucocorticoid receptors (GRs) in the reward system affects the rewarding value of a high-fat diet (HFD). To do so, we generated mice that lack functional GRs specifically in dopaminergic neurons (D-KO mice) or corticostriatal neurons (CS-KO mice), subjected the mice to caloric restriction stress conditions, and evaluated the rewarding value of a HFD by conditioned place preference (CPP) test. Caloric restriction induced increases in serum corticosterone to similar levels in all genotypes. While CS-KO as well as WT mice exhibited a significant preference for HFD in the CPP test, D-KO mice exhibited no such preference. There were no differences between WT and D-KO mice in consumption of HFD after fasting or cognitive function evaluated by a novel object recognition test. These data suggest that glucocorticoid signaling in the VTA increases the rewarding value of a HFD under restricted caloric stress.

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  17. CD4(+) T cells are essential for the development of destructive thyroiditis induced by anti-PD-1 antibody in thyroglobulin-immunized mice 国際誌

    Yasuda Yoshinori, Iwama Shintaro, Sugiyama Daisuke, Okuji Takayuki, Kobayashi Tomoko, Ito Masaaki, Okada Norio, Enomoto Atsushi, Ito Sachiko, Yan Yue, Sugiyama Mariko, Onoue Takeshi, Tsunekawa Taku, Ito Yoshihiro, Takagi Hiroshi, Hagiwara Daisuke, Goto Motomitsu, Suga Hidetaka, Banno Ryoichi, Takahashi Masahide, Nishikawa Hiroyoshi, Arima Hiroshi

    SCIENCE TRANSLATIONAL MEDICINE   13 巻 ( 593 )   2021年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Science Translational Medicine  

    Immune-related adverse events induced by anti–programmed cell death–1 antibodies (PD-1-Ab), including destructive thyroiditis (thyroid-irAE), are thought to be caused by activated T cells. However, the T cell subsets that are directly responsible for damaging self-organs remain unclear. To clarify which T cell subsets are involved in the development of thyroid-irAE, a mouse model of thyroid-irAE was analyzed. PD-1-Ab administration 2.5 months after immunization with thyroglobulin caused destructive thyroiditis. Thyroiditis was completely prevented by previous depletion of CD4+ T cells and partially prevented by depleting CD8+ T cells. The frequencies of central and effector memory CD4+ T cell subsets and the secretion of interferon-y after stimulation with thyroglobulin were increased in the cervical lymph nodes of mice with thyroid-irAE compared with controls. Histopathological analysis revealed infiltration of CD4+ T cells expressing granzyme B in thyroid glands and major histocompatibility complex class II expression on thyrocytes in mice with thyroid-irAE. Adoptive transfer of CD4+ T cells from cervical lymph nodes in mice with thyroid-irAE caused destruction of thyroid follicular architecture in the irradiated recipient mice. Flow cytometric analyses showed that the frequencies of central and effector memory CD4+ T cells expressing the cytotoxic marker CD27 were higher in peripheral blood mononuclear cells collected from patients with thyroid-irAE induced by PD-1-Ab versus those without. These data suggest a critical role for cytotoxic memory CD4+ T cells activated by PD-1-Ab in the pathogenesis of thyroid-irAE.

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  18. High-fat Feeding Causes Inflammation and Insulin Resistance in the Ventral Tegmental Area in Mice 国際誌

    Mizoguchi Akira, Banno Ryoichi, Sun Runan, Yaginuma Hiroshi, Taki Keigo, Kobayashi Tomoko, Sugiyama Mariko, Tsunekawa Taku, Onoue Takeshi, Takagi Hiroshi, Hagiwara Daisuke, Ito Yoshihiro, Iwama Shintaro, Suga Hidetaka, Arima Hiroshi

    NEUROSCIENCE   461 巻   頁: 72 - 79   2021年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Neuroscience  

    The reward system plays an important role in the pathogenesis of not only drug addiction, but also diet-induced obesity. Recent studies have shown that insulin and leptin receptor signaling in the ventral tegmental area (VTA) regulate energy homeostasis and that their dysregulation is responsible for obesity and altered food preferences. Although a high-fat diet (HFD) induces inflammation that leads to insulin and leptin resistance in the brain, it remains unclear whether HFD induces inflammation in the VTA. In the present study, we placed male mice on a chow diet or HFD for 3, 7, and 28 days and evaluated the mRNA expression of inflammatory cytokines and microglial activation markers in the VTA. The HFD group showed significantly elevated mRNA expressions of IL1β at 3 days; tumor necrosis factor-alpha (TNFα), IL1β, IL6, Iba1, and CD11b at 7 days; and TNFα, IL1β, Iba1, and CD11b at 28 days. The changes in TNFα were also confirmed in immunohistochemical analysis. Next, after administration of chow or HFD for 7 days, we selected mice with equal weights in both groups. In experiments using these mice, Akt phosphorylation in the VTA was significantly decreased after intracerebroventricular injection of insulin, whereas no change in STAT3 phosphorylation was found with leptin. Taken together, these results suggest that HFD induces inflammation at least partly associated with microglial activation in the VTA leading to insulin resistance, independently of the energy balance. Our data provide new insight into the pathophysiology of obesity caused by a dysfunctional reward system under HFD conditions.

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  19. Arginine vasopressin-Venus reporter mice as a tool for studying magnocellular arginine vasopressin neurons 国際誌

    Hagiwara Daisuke, Tochiya Masayoshi, Azuma Yoshinori, Tsumura Tetsuro, Hodai Yuichi, Kawaguchi Yohei, Miyata Takashi, Kobayashi Tomoko, Sugiyama Mariko, Onoue Takeshi, Takagi Hiroshi, Ito Yoshihiro, Iwama Shintaro, Suga Hidetaka, Banno Ryoichi, Arima Hiroshi

    PEPTIDES   139 巻   頁: 170517 - 170517   2021年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Peptides  

    Arginine vasopressin (AVP) synthesized in the magnocellular neurons of the hypothalamus is transported through their axons and released from the posterior pituitary into the systemic circulation to act as an antidiuretic hormone. AVP synthesis and release are precisely regulated by changes in plasma osmolality. Magnocellular AVP neurons receive innervation from osmosensory and sodium-sensing neurons, but previous studies showed that AVP neurons per se are osmosensitive as well. In the current study, we made AVP-Venus reporter mice and showed that Venus was expressed exclusively in AVP neurons and was upregulated under water deprivation. In hypothalamic organotypic cultures from the AVP-Venus mice, Venus-labeled AVP neurons in the supraoptic and paraventricular nuclei survived for 1 month, and Venus expression was upregulated by forskolin. Furthermore, in dissociated Venus-labeled magnocellular neurons, treatment with NaCl, but not with mannitol, decreased Venus fluorescence in the soma of the AVP neurons. Thus, Venus expression in AVP-Venus transgenic mice, as well as in primary cultures, faithfully showed the properties of intrinsic AVP expression. These findings indicate that AVP-Venus mice as well as the primary hypothalamic cultures could be useful for studying magnocellular AVP neurons.

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  20. Anti-pituitary antibodies and susceptible human leukocyte antigen alleles as predictive biomarkers for pituitary dysfunction induced by immune checkpoint inhibitors 国際誌

    Kobayashi Tomoko, Iwama Shintaro, Sugiyama Daisuke, Yasuda Yoshinori, Okuji Takayuki, Ito Masaaki, Ito Sachiko, Sugiyama Mariko, Onoue Takeshi, Takagi Hiroshi, Hagiwara Daisuke, Ito Yoshihiro, Suga Hidetaka, Banno Ryoichi, Nishikawa Hiroyoshi, Arima Hiroshi

    JOURNAL FOR IMMUNOTHERAPY OF CANCER   9 巻 ( 5 )   2021年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal for ImmunoTherapy of Cancer  

    Background Pituitary dysfunction is a life-threatening immune-related adverse event (irAE) induced by immune checkpoint inhibitors (ICIs). To date, it is not possible to identify patients who may develop pituitary irAEs prior to ICI treatment. The aim of this study was to characterize the predisposition for ICI-induced pituitary irAEs by analyzing anti-pituitary antibodies (APAs) and human leukocyte antigens (HLAs). Methods In this case-control study, APAs and HLA alleles were analyzed in 62 patients (17 who developed ICI-induced isolated adrenocorticotropic hormone deficiency (ICI-IAD), 5 who developed ICI-induced hypophysitis (ICI-H) and 40 who did not develop pituitary irAEs) treated with ICIs between November 2, 2015, and March 31, 2020, at Nagoya University Hospital. The main outcome measures in this study were the association between the development of pituitary irAEs with APAs at baseline and after treatment and HLA alleles. Results Eleven of 17 (64.7%) patients who developed ICI-IAD had APAs at baseline, whereas APAs were positive only in 1 of 40 (2.5%) control patients. Although APAs were negative at baseline in all patients who developed ICI-H, they had become positive before the onset of ICI-H in 3 of 4 patients several weeks after ipilimumab administration. At the onset of ICI-IAD and ICI-H, APAs were positive in 15 of 17 (88.2%) and 4 of 5 (80%) patients, respectively. The prevalence of HLA-Cw12, HLA-DR15, HLA-DQ7, and HLA-DPw9 was significantly higher in patients with ICI-IAD, whereas that of HLA-Cw12 and HLA-DR15 was significantly higher in patients with ICI-H than in controls. Conclusions This study showed distinct and overlapped patterns of APAs and HLA alleles between ICI-IAD and ICI-H. Our findings also showed that positive APAs at baseline and after treatment, together with susceptible HLA alleles, could become predictive biomarkers for ICI-IAD and ICI-H, respectively. Trial registration number UMIN000019024.

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  21. Dietary sodium chloride attenuates increased beta-cell mass to cause glucose intolerance in mice under a high-fat diet 国際誌

    Taki Keigo, Takagi Hiroshi, Hirose Tomonori, Sun Runan, Yaginuma Hiroshi, Mizoguchi Akira, Kobayashi Tomoko, Sugiyama Mariko, Tsunekawa Taku, Onoue Takeshi, Hagiwara Daisuke, Ito Yoshihiro, Iwama Shintaro, Suga Hidetaka, Banno Ryoichi, Sakano Daisuke, Kume Shoen, Arima Hiroshi

    PLOS ONE   16 巻 ( 3 ) 頁: e0248065   2021年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PLoS ONE  

    Excessive sodium salt (NaCl) or fat intake is associated with a variety of increased health risks. However, whether excessive NaCl intake accompanied by a high-fat diet (HFD) affects glucose metabolism has not been elucidated. In this study, C57BL/6J male mice were fed a normal chow diet (NCD), a NCD plus high-NaCl diet (NCD plus NaCl), a HFD, or a HFD plus high-NaCl diet (HFD plus NaCl) for 30 weeks. No significant differences in body weight gain, insulin sensitivity, and glucose tolerance were observed between NCD-fed and NCD plus NaCl-fed mice. In contrast, body and liver weights were decreased, but the weight of epididymal white adipose tissue was increased in HFD plus NaCl-fed compared to HFDfed mice. HFD plus NaCl-fed mice had lower plasma glucose levels in an insulin tolerance test, and showed higher plasma glucose and lower plasma insulin levels in an intraperitoneal glucose tolerance test compared to HFD-fed mice. The β-cell area and number of islets were decreased in HFD plus NaCl-fed compared to HFD-fed mice. Increased Ki67-positive β-cells, and increased expression levels of Ki67, CyclinB1, and CyclinD1 mRNA in islets were observed in HFD-fed but not HFD plus NaCl-fed mice when compared to NCD-fed mice. Our data suggest that excessive NaCl intake accompanied by a HFD exacerbates glucose intolerance, with impairment in insulin secretion caused by the attenuation of expansion of β-cell mass in the pancreas. Copyright:

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  22. Peripheral combination treatment of leptin and an SGLT2 inhibitor improved glucose metabolism in insulin-dependent diabetes mellitus mice

    Yaginuma Hiroshi, Banno Ryoichi, Sun Runan, Taki Keigo, Mizoguchi Akira, Kobayashi Tomoko, Sugiyama Mariko, Tsunekawa Taku, Onoue Takeshi, Takagi Hiroshi, Hagiwara Daisuke, Ito Yoshihiro, Iwama Shintaro, Suga Hidetaka, Arima Hiroshi

    JOURNAL OF PHARMACOLOGICAL SCIENCES   147 巻 ( 4 ) 頁: 340 - 347   2021年

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    記述言語:日本語   出版者・発行元:Journal of Pharmacological Sciences  

    We investigated whether peripheral combination treatment of a sodium–glucose cotransporter 2 (SGLT2) inhibitor and leptin improves glucose metabolism in insulin-dependent diabetes mellitus (IDDM) model mice. Twelve-week-old male C57BL6 mice were intraperitoneally administered a high dose of streptozotocin to produce IDDM. IDDM mice were then divided into five groups: SGLT2 inhibitor treatment alone, leptin treatment alone, leptin and SGLT2 inhibitor co-treatment, untreated IDDM mice, and healthy mice groups. The blood glucose (BG) level at the end of the dark cycle was measured, and a glucose tolerance test (GTT) was performed and compared between the five groups. Leptin was peripherally administered at 20 μg/day using an osmotic pump, and an SGLT2 inhibitor, ipragliflozin, was orally administered at 3 mg/kg/day. Monotherapy with SGLT2 inhibitor or leptin significantly improved glucose metabolism in mice as evaluated by BG and GTT compared with the untreated group, whereas the co-treatment group with SGLT2 inhibitor and leptin further improved glucose metabolism as compared with the monotherapy group. Notably, glucose metabolism in the co-treatment group improved to the same level as that in the healthy mice group. Thus, peripheral combination treatment with leptin and SGLT2 inhibitor improved glucose metabolism in IDDM mice without the use of insulin.

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  23. Endoplasmic reticulum chaperone BiP/GRP78 knockdown leads to autophagy and cell death of arginine vasopressin neurons in mice 国際誌

    Kawaguchi Yohei, Hagiwara Daisuke, Miyata Takashi, Hodai Yuichi, Kurimoto Junki, Takagi Hiroshi, Suga Hidetaka, Kobayashi Tomoko, Sugiyama Mariko, Onoue Takeshi, Ito Yoshihiro, Iwama Shintaro, Banno Ryoichi, Grinevich Valery, Arima Hiroshi

    SCIENTIFIC REPORTS   10 巻 ( 1 ) 頁: 19730 - 19730   2020年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Scientific Reports  

    The immunoglobulin heavy chain binding protein (BiP), also referred to as 78-kDa glucose-regulated protein (GRP78), is a pivotal endoplasmic reticulum (ER) chaperone which modulates the unfolded protein response under ER stress. Our previous studies showed that BiP is expressed in arginine vasopressin (AVP) neurons under non-stress conditions and that BiP expression is upregulated in proportion to the increased AVP expression under dehydration. To clarify the role of BiP in AVP neurons, we used a viral approach in combination with shRNA interference for BiP knockdown in mouse AVP neurons. Injection of a recombinant adeno-associated virus equipped with a mouse AVP promoter and BiP shRNA cassette provided specific BiP knockdown in AVP neurons of the supraoptic (SON) and paraventricular nuclei (PVN) in mice. AVP neuron-specific BiP knockdown led to ER stress and AVP neuronal loss in the SON and PVN, resulting in increased urine volume due to lack of AVP secretion. Immunoelectron microscopy of AVP neurons revealed that autophagy was activated through the process of AVP neuronal loss, whereas no obvious features characteristic of apoptosis were observed. Pharmacological inhibition of autophagy by chloroquine exacerbated the AVP neuronal loss due to BiP knockdown, indicating a protective role of autophagy in AVP neurons under ER stress. In summary, our results demonstrate that BiP is essential for the AVP neuron system.

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  24. Degradation of Mutant Protein Aggregates within the Endoplasmic Reticulum of Vasopressin Neurons 国際誌

    Miyata Takashi, Hagiwara Daisuke, Hodai Yuichi, Miwata Tsutomu, Kawaguchi Yohei, Kurimoto Junki, Ozaki Hajime, Mitsumoto Kazuki, Takagi Hiroshi, Suga Hidetaka, Kobayashi Tomoko, Sugiyama Mariko, Onoue Takeshi, Ito Yoshihiro, Iwama Shintaro, Banno Ryoichi, Matsumoto Mami, Kawakami Natsuko, Ohno Nobuhiko, Sakamoto Hirotaka, Arima Hiroshi

    ISCIENCE   23 巻 ( 10 ) 頁: 101648 - 101648   2020年10月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:iScience  

    Misfolded or unfolded proteins in the ER are said to be degraded only after translocation or isolation from the ER. Here, we describe a mechanism by which mutant proteins are degraded within the ER. Aggregates of mutant arginine vasopressin (AVP) precursor were confined to ER-associated compartments (ERACs) connected to the ER in AVP neurons of a mouse model of familial neurohypophysial diabetes insipidus. The ERACs were enclosed by membranes, an ER chaperone and marker protein of phagophores and autophagosomes were expressed around the aggregates, and lysosomes fused with the ERACs. Moreover, lysosome-related molecules were present within the ERACs, and aggregate degradation within the ERACs was dependent on autophagic-lysosomal activity. Thus, we demonstrate that protein aggregates can be degraded by autophagic-lysosomal machinery within specialized compartments of the ER.

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  25. Peripheral combination treatment of leptin and SGLT2 inhibitor improved glucose metabolism in insulin-dependent diabetes mice

    Yaginuma H., Banno R., Sun R., Taki K., Sugiyama M., Tsunekawa T., Takagi H., Ito Y., Arima H.

    DIABETOLOGIA   63 巻 ( SUPPL 1 ) 頁: S259 - S260   2020年9月

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  26. Protein tyrosine phosphatase 1B deficiency enhances leptin action to improve glucose homeostasis in IDDM treatment with leptin

    Ito Y., Banno R., Sun R., Yaginuma H., Taki K., Sugiyama M., Tsunekawa T., Takagi H., Arima H.

    DIABETOLOGIA   63 巻 ( SUPPL 1 ) 頁: S12 - S12   2020年9月

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  27. The regulation of glucose metabolism by astrocytes in diet induced obesity mice

    Sugiyama M., Banno R., Sun R., Yaginuma H., Taki K., Takagi H., Ito Y., Yamanaka K., Arima H.

    DIABETOLOGIA   63 巻 ( SUPPL 1 ) 頁: S266 - S266   2020年9月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  28. Hypothalamic glial cells isolated by MACS reveal that microglia and astrocytes induce hypothalamic inflammation via different processes under high-fat diet conditions 国際誌

    Sugiyama Mariko, Banno Ryoichi, Yaginuma Hiroshi, Taki Keigo, Mizoguchi Akira, Tsunekawa Taku, Onoue Takeshi, Takagi Hiroshi, Ito Yoshihiro, Iwama Shintaro, Goto Motomitsu, Suga Hidetaka, Komine Okiru, Yamanaka Koji, Arima Hiroshi

    NEUROCHEMISTRY INTERNATIONAL   136 巻   頁: 104733 - 104733   2020年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Neurochemistry International  

    Glial cells can mediate hypothalamic inflammatory processes induced in response to a high-fat diet (HFD). We used magnetic-activated cell sorting (MACS) to isolate microglia and astrocytes from hypothalamus of mice fed HFD and examined changes in expression of inflammation-related cytokines and markers related to glial cell activation status. Hypothalamus from male C57BL6 mice fed a chow diet (chow) or HFD for 1, 3, or 28 days were collected and microglia and astrocytes were isolated by MACS. After confirming cell viability by fluorescence activated cell sorting, mRNA expression levels of inflammation-related cytokines and markers of glial cell activation status were examined by qRT-PCR, which revealed that both glial cell types isolated by MACS retained specificity. On day 3 of HFD, both CD86 and TNFα mRNA expression was significantly increased in microglia relative to the chow group. In astrocytes, TNFα mRNA expression levels were similar between the chow and HFD groups on day 3, but anti-inflammatory cytokine IL-10 levels were significantly increased. On day 7 of HFD, TNFα expression in microglia decreased to levels comparable to the chow group while that in astrocytes remained unchanged. On day 28 of HFD, TNFα levels were significantly increased in both microglia and astrocytes, which had increased mRNA expression of CD86 and MAO-B, respectively. For both glial cell types, results for TNFα expression assessed by RT-PCR and immunohistochemical analysis were similar. These results indicate that the role of microglia and astrocytes in hypothalamic inflammation under HFD conditions changed with time and these changes were accompanied by changes in the activation status of glial cells. Our data suggest that early after initiating HFD, hypothalamic astrocytes suppress diet-induced inflammation at least in part by secreting IL-10, whereas continued HFD feeding impairs this suppressive function such that both microglia and astrocytes promote hypothalamic inflammation.

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  29. Anti-thyroid antibodies and thyroid echo pattern at baseline as risk factors for thyroid dysfunction induced by anti-programmed cell death-1 antibodies: a prospective study 国際誌

    Okada Norio, Iwama Shintaro, Okuji Takayuki, Kobayashi Tomoko, Yasuda Yoshinori, Wada Eri, Onoue Takeshi, Goto Motomitsu, Sugiyama Mariko, Tsunekawa Taku, Takagi Hiroshi, Hagiwara Daisuke, Ito Yoshihiro, Suga Hidetaka, Banno Ryoichi, Hase Tetsunari, Morise Masahiro, Kanda Mitsuro, Yokota Kenji, Hashimoto Naozumi, Ando Masahiko, Fujimoto Yasushi, Nagino Masato, Kodera Yasuhiro, Fujishiro Mitsuhiro, Hibi Hideharu, Sone Michihiko, Kiyoi Hitoshi, Gotoh Momokazu, Ando Yuichi, Akiyama Masashi, Hasegawa Yoshinori, Arima Hiroshi

    BRITISH JOURNAL OF CANCER   122 巻 ( 6 ) 頁: 771 - 777   2020年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:British Journal of Cancer  

    Background: Anti-programmed cell death-1 (PD-1) antibodies can cause thyroid dysfunction. However, no predictive biomarkers enabling stratification of thyroid dysfunction risk have been identified. Methods: A total of 209 patients treated with an anti-PD-1 antibody were evaluated for anti-thyroid antibodies at baseline and prospectively for thyroid function every 6 weeks for 24 weeks after treatment initiation, and then observed until the visits stopped. Thyroid ultrasonography was performed if the patient was positive for anti-thyroid antibodies at baseline. Results: Of the 209 patients, 19 (9.1%) developed thyroid dysfunction (destructive thyroiditis or hypothyroidism). The cumulative incidence of thyroid dysfunction was significantly higher in patients who were positive vs. negative for anti-thyroid antibodies (15/44 [34.1%] vs. 4/165 [2.4%], p < 0.001). Forty-two patients positive for anti-thyroid antibodies at baseline were divided into two groups according to the presence of an irregular echo pattern. The cumulative incidence of thyroid dysfunction was significantly higher in those with an irregular vs. a regular echo pattern (13/23 [56.5%] vs. 1/19 [5.3%], p = 0.001). None of the patients developed thyroid dysfunction after the initial 24-week period. Conclusions: The risk of thyroid dysfunction induced by anti-PD-1 antibodies can be predicted by evaluation of anti-thyroid antibodies and the thyroid echo pattern at baseline. Trial registration: UMIN000019024.

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  30. Flash glucose monitoring helps achieve better glycemic control than conventional self-monitoring of blood glucose in non-insulin-treated type 2 diabetes: a randomized controlled trial 国際誌

    Wada Eri, Onoue Takeshi, Kobayashi Tomoko, Handa Tomoko, Hayase Ayaka, Ito Masaaki, Furukawa Mariko, Okuji Takayuki, Okada Norio, Iwama Shintaro, Sugiyama Mariko, Tsunekawa Taku, Takagi Hiroshi, Hagiwara Daisuke, Ito Yoshihiro, Suga Hidetaka, Banno Ryoichi, Kuwatsuka Yachiyo, Ando Masahiko, Goto Motomitsu, Arima Hiroshi

    BMJ OPEN DIABETES RESEARCH & CARE   8 巻 ( 1 )   2020年1月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BMJ open diabetes research &amp; care  

    INTRODUCTION: The present study aimed to evaluate the effects of flash glucose monitoring (FGM) and conventional self-monitoring of blood glucose (SMBG) on glycemic control in patients with non-insulin-treated type 2 diabetes. RESEARCH DESIGN AND METHODS: In this 24-week, multicenter, open-label, randomized (1:1), parallel-group study, patients with non-insulin-treated type 2 diabetes at five hospitals in Japan were randomly assigned to the FGM (n=49) or SMBG (n=51) groups and were provided each device for 12 weeks. The primary outcome was change in glycated hemoglobin (HbA1c) level, and was compared using analysis of covariance model that included baseline values and group as covariates. RESULTS: Forty-eight participants in the FGM group and 45 in the SMBG group completed the study. The mean HbA1c levels were 7.83% (62.1 mmol/mol) in the FGM group and 7.84% (62.2 mmol/mol) in the SMBG group at baseline, and the values were reduced in both FGM (-0.43% (-4.7 mmol/mol), p<0.001) and SMBG groups (-0.30% (-3.3 mmol/mol), p=0.001) at 12 weeks. On the other hand, HbA1c was significantly decreased from baseline values in the FGM group, but not in the SMBG group at 24 weeks (FGM: -0.46% (-5.0 mmol/mol), p<0.001; SMBG: -0.17% (-1.8 mmol/mol), p=0.124); a significant between-group difference was also observed (difference -0.29% (-3.2 mmol/mol), p=0.022). Diabetes Treatment Satisfaction Questionnaire score was significantly improved, and the mean glucose levels, SD of glucose, mean amplitude of glycemic excursions and time in hyperglycemia were significantly decreased in the FGM group compared with the SMBG group. CONCLUSIONS: Glycemic control was better with FGM than with SMBG after cessation of glucose monitoring in patients with non-insulin-treated type 2 diabetes. TRIAL REGISTRATION NUMBER: UMIN000026452, jRCTs041180082.

    DOI: 10.1136/bmjdrc-2019-001115

    Web of Science

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    PubMed

  31. Pituitary dysfunction induced by immune checkpoint inhibitors is associated with better overall survival in both malignant melanoma and non-small cell lung carcinoma: a prospective study 国際誌

    Kobayashi Tomoko, Iwama Shintaro, Yasuda Yoshinori, Okada Norio, Okuji Takayuki, Ito Masaaki, Onoue Takeshi, Goto Motomitsu, Sugiyama Mariko, Tsunekawa Taku, Takagi Hiroshi, Hagiwara Daisuke, Ito Yoshihiro, Suga Hidetaka, Banno Ryoichi, Yokota Kenji, Hase Tetsunari, Morise Masahiro, Hashimoto Naozumi, Ando Masahiko, Fujimoto Yasushi, Hibi Hideharu, Sone Michihiko, Ando Yuichi, Akiyama Masashi, Hasegawa Yoshinori, Arima Hiroshi

    JOURNAL FOR IMMUNOTHERAPY OF CANCER   8 巻 ( 2 )   2020年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal for ImmunoTherapy of Cancer  

    Background Several immune-related adverse events (irAEs) are reported to be associated with therapeutic efficacy of immune checkpoint inhibitors, yet whether pituitary dysfunction, a life-threatening irAE, affects overall survival (OS) in patients with malignancies is unclear. This prospective study examined the association of pituitary dysfunction (pituitary-irAE) with OS of patients with non-small cell lung carcinoma (NSCLC) or malignant melanoma (MM). Methods A total of 174 patients (NSCLC, 108; MM, 66) treated with ipilimumab, nivolumab, pembrolizumab, or atezolizumab at Nagoya University Hospital were evaluated for OS and the development of pituitary-irAE. Kaplan-Meier curves of OS as a function of the development of pituitary-irAE were produced with the log-rank test as a primary endpoint. Results Pituitary-irAE was observed in 16 patients (4 (3.7%) with NSCLC, 12 (18.2%) with MM) having two different disease types: hypophysitis with deficiency of multiple anterior pituitary hormones accompanied by pituitary enlargement, and isolated adrenocorticotropic hormone (ACTH) deficiency without pituitary enlargement. Among these patients, 6 developed pituitary-irAE while being treated with ipilimumab (6/25 patients (24.0%) treated with ipilimumab) and 10 developed pituitary-irAE during treatment with nivolumab or pembrolizumab (10/167 (6.0%)). All 16 patients had ACTH deficiency and were treated with physiological doses of hydrocortisone. The development of pituitary-irAE was associated with better OS in patients with NSCLC (not reached vs 441 (95% CI not calculated) days, p<0.05) and MM (885 (95% CI 434 to 1336) vs 298 (95% CI 84 to 512) days, p<0.05). Conclusions In our study cohort, the incidence of pituitary-irAE was higher than previously reported and the development of pituitary-irAE predicted better prognosis for both NSCLC and MM when patients were treated with physiological doses of hydrocortisone. Clinical trials registration UMIN000019024.

    DOI: 10.1136/jitc-2020-000779

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共同研究・競争的資金等の研究課題 1

  1. アストロサイトにおけるprotein tyrosine phosphatase-1Bの役割について

    2019年1月 - 2020年1月

    鈴木謙三記念医科学応用研究財団  調査研究助成 

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    資金種別:競争的資金

科研費 2

  1. 自発運動が食事誘発性肥満マウスの視床下部炎症を抑える細胞・分子メカニズムの研究

    研究課題/研究課題番号:21K16368  2021年4月 - 2023年3月

    若手研究

    杉山 摩利子

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    担当区分:研究代表者 

    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    肥満発症の機序として、高脂肪食(HFD)を摂取すると体重増加に先行してグリア細胞の活性化が生じる。その結果、視床下部で炎症が惹起され体重調節を担う視床下部ニューロンに機能異常が生じることで肥満形成の起点となることが知られている。肥満治療に用いられる運動療法は、HFD摂取に伴う視床下部炎症に対して抑制的に働くが、その詳細な機序は明らかではない。本研究では、HFD投与下でマウス用ホイールを用いた自発運動を行い、運動負荷が視床下部のグリアに与える影響を検討する。HFD投与に伴う視床下部炎症に対し運動療法が与える影響についてその分子機序を明らかにすることで肥満症に対する新たな運動処方の開発に繋げる。

  2. AgRPニューロンにおけるプロテインフォスファターゼ1Bの作用解析

    研究課題/研究課題番号:19K18005  2019年4月 - 2021年3月

    科学研究費助成事業  若手研究

    杉山 摩利子

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    担当区分:研究代表者 

    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

    視床下部は糖およびエネルギー代謝調節を担う重要な器官である。脂肪細胞および膵臓から分泌されるレプチン、インスリンは視床下部の弓状核に存在するPOMCニューロンおよびAgRPニューロンに直接作用し血糖降下、体重減少作用を発揮する。PTP1Bはレプチンおよびインスリン受容体シグナルを阻害する蛋白であり全身性、脳特異的もしくはPOMCニューロン特異的にPTP1Bを欠損させると高脂肪食投与に対して肥満抵抗性を来し糖代謝は改善する。一方、AgRPニューロンにおけるPTP1Bの役割は未だ明らかではないため本研究ではAgRPニューロンにおけるPTP1Bが糖およびエネルギー代謝調節に与える影響を明らかにする。
    1型糖尿病モデル(IDDM)マウスにおいてレプチンによる血糖降下作用の機序解明の目的で、AgRPもしくはPOMCニューロン特異的にProtein Tyrosine Phosphatase 1Bを欠損させたマウスを作成し、ストレプトゾトシンを腹腔内投与してIDDMマウスを作成後、レプチンを末梢投与して糖代謝に与える影響を検討した。AgRP KOマウスではレプチンによる血糖降下作用は野生型と比較してわずかに認められたのみであったが、POMC KOマウスにおいては血糖降下作用が野生型と比較して有意であることが確認された。
    抗PTP1B薬はインスリン、レプチンシグナルを改善する薬剤として糖尿病治療薬として臨床治験中である。本研究ではIDDMモデルマウスにおいて、中枢において糖代謝を司るPOMCおよびAgRPニューロン特異的にPTP1Bを欠損させたモデルマウスを用いて糖代謝を評価した。本研究の結果は抗PTP1B薬の作用機序の解明に寄与し、また治療選択肢の乏しいIDDM患者において新たな治療戦略の提示につながり社会的な貢献は大きい。