2024/03/15 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 4

  1. 肥満

  2. 糖尿病

  3. 内分泌

  4. 肥満 炎症 視床下部 報酬系 内分泌 糖尿病

研究分野 1

  1. ライフサイエンス / 代謝、内分泌学

経歴 3

  1. 名古屋大学医学部附属病院   糖尿病・内分泌内科   助教

    2020年4月 - 現在

  2. 名古屋大学医学部附属病院   糖尿病・内分泌内科   病院助教

    2018年4月 - 2020年3月

  3. 名古屋大学医学部附属病院   糖尿病・内分泌内科   医員

    2015年4月 - 2018年3月

学歴 3

  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. 名古屋大学大学院   医学系研究科   糖尿病・内分泌内科学

    2014年4月 - 2018年3月

  3. 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 6

  1. 日本内分泌学会

  2. 日本内科学会

  3. 日本間脳下垂体腫瘍学会

  4. 日本肥満学会

  5. 日本糖尿病学会

  6. 日本甲状腺学会

▼全件表示

 

論文 53

  1. GABA<sub>B</sub> Receptor Signaling in the Mesolimbic System Suppresses Binge-like Consumption of a High-Fat Diet 国際誌

    Tsunekawa, T; Banno, R; Yaginuma, H; Taki, K; Mizoguchi, A; Sugiyama, M; Onoue, T; Takagi, H; Hagiwara, D; Ito, Y; Iwama, S; Goto, M; Suga, H; Bettler, B; Arima, H

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

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    記述言語:英語   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 <i>AgRP</i> mRNA expression under high-fat diet conditions 国際誌

    Sugiyama, M; Banno, R; Mizoguchi, A; Tominaga, T; Tsunekawa, T; Onoue, T; Hagiwara, D; Ito, Y; Morishita, Y; Iwama, S; Goto, M; Suga, H; Arima, H

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

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    記述言語:英語   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, 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

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

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    記述言語:英語   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 <i>In Vitro</i> Using 3D-Cultured Human iPS Cells 国際誌

    Kasai, T; Suga, H; Sakakibara, M; Ozone, C; Matsumoto, R; Kano, M; Mitsumoto, K; Ogawa, K; Kodani, Y; Nagasaki, H; Inoshita, N; Sugiyama, M; Onoue, T; Tsunekawa, T; Ito, Y; Takagi, H; Hagiwara, D; Iwama, S; Goto, M; Banno, R; Takahashi, J; Arima, H

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

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    記述言語:英語   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, T; Goto, M; Wada, E; Furukawa, M; Okuji, T; Okada, N; Kobayashi, T; Iwama, S; Sugiyama, M; Tsunekawa, T; Takagi, H; Hagiwara, D; Ito, Y; Morishita, Y; Seino, Y; Suga, H; Banno, R; Hamada, Y; Ando, M; Yamamori, E; Arima, H

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

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    記述言語:英語   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, H; Hagiwara, D; Handa, T; Sugiyama, M; Onoue, T; Tsunekawa, T; Ito, Y; Iwama, S; Goto, M; Suga, H; Banno, R; Takahashi, K; Matsui, S; Arima, H

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

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    記述言語:英語   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, K; Suga, H; Sakakibara, M; Soen, M; Yamada, T; Ozaki, H; Nagai, T; Kano, M; Kasai, T; Ozone, C; Ogawa, K; Sugiyama, M; Onoue, T; Tsunekawa, T; Takagi, H; Hagiwara, D; Ito, Y; Iwama, S; Goto, M; Banno, R; Arima, H

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

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    記述言語:英語   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, M; Suga, H; Ishihara, T; Sakakibara, M; Soen, M; Yamada, T; Ozaki, H; Mitsumoto, K; Kasai, T; Sugiyama, M; Onoue, T; Tsunekawa, T; Takagi, H; Hagiwara, D; Ito, Y; Iwama, S; Goto, M; Banno, R; Arima, H

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

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    記述言語:英語   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, T; Goto, M; Onoue, T; Mizoguchi, A; Sugiyama, M; Tsunekawa, T; Hagiwara, D; Morishita, Y; Ito, Y; Iwama, S; Suga, H; Banno, R; Arima, H

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

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    記述言語:英語   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. Improved glycemic control after the use of flash glucose monitoring accompanied by improved treatment satisfaction in patients with non-insulin-treated type 2 diabetes: A post-hoc analysis of a randomized controlled trial 国際誌

    Hayase, A; Onoue, T; Kobayashi, T; Wada, E; Handa, T; Kinoshita, T; Yamagami, A; Yasuda, Y; Iwama, S; Kawaguchi, Y; Miyata, T; Sugiyama, M; Takagi, H; Hagiwara, D; Suga, H; Banno, R; Kuwatsuka, Y; Ando, M; Goto, M; Arima, H

    PRIMARY CARE DIABETES   17 巻 ( 6 ) 頁: 575 - 580   2023年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Primary Care Diabetes  

    Aims: In our previously reported randomized controlled trial in patients with noninsulin-treated type 2 diabetes, the use of flash glucose monitoring (FGM) improved glycated hemoglobin (HbA1c), and the improvement was sustained after the cessation of glucose monitoring. In this post-hoc analysis, we examined data from our trial to identify the factors that influenced FGM efficacy. Methods: We analyzed data for 48 of 49 participants of the FGM group who completed the trial to clarify the changes in various parameters and factors related to HbA1c improvement with the use of FGM. Results: Analyses of the FGM data during the 12-week FGM provision period showed that the weekly mean blood glucose levels considerably decreased as early as at 1 week compared with the baseline values, and this decline continued for 12 weeks. An enhancement in the Diabetes Treatment Satisfaction Questionnaire regarding “willingness to continue the current treatment” score was significantly associated with the improvement in HbA1c at 12 (p = 0.009) and 24 weeks (p = 0.012). Conclusions: Glycemic control was improved soon after FGM initiation, accompanied by improved satisfaction with continuation of the current treatment in patients with noninsulin-treated type 2 diabetes.

    DOI: 10.1016/j.pcd.2023.09.009

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  11. Generation and purification of ACTH-secreting hPSC-derived pituitary cells for effective transplantation

    Taga, S; Suga, H; Nakano, T; Kuwahara, A; Inoshita, N; Kodani, Y; Nagasaki, H; Sato, Y; Tsumura, Y; Sakakibara, M; Soen, M; Miwata, T; Ozaki, H; Kano, M; Watari, K; Ikeda, A; Yamanaka, M; Takahashi, Y; Kitamoto, S; Kawaguchi, Y; Miyata, T; Kobayashi, T; Sugiyama, M; Onoue, T; Yasuda, Y; Hagiwara, D; Iwama, S; Tomigahara, Y; Kimura, T; Arima, H

    STEM CELL REPORTS   18 巻 ( 8 ) 頁: 1657 - 1671   2023年8月

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    記述言語:英語   出版者・発行元:Stem Cell Reports  

    Pituitary organoids are promising graft sources for transplantation in treatment of hypopituitarism. Building on development of self-organizing culture to generate pituitary-hypothalamic organoids (PHOs) using human pluripotent stem cells (hPSCs), we established techniques to generate PHOs using feeder-free hPSCs and to purify pituitary cells. The PHOs were uniformly and reliably generated through preconditioning of undifferentiated hPSCs and modulation of Wnt and TGF-β signaling after differentiation. Cell sorting using EpCAM, a pituitary cell-surface marker, successfully purified pituitary cells, reducing off-target cell numbers. EpCAM-expressing purified pituitary cells reaggregated to form three-dimensional pituitary spheres (3D-pituitaries). These exhibited high adrenocorticotropic hormone (ACTH) secretory capacity and responded to both positive and negative regulators. When transplanted into hypopituitary mice, the 3D-pituitaries engrafted, improved ACTH levels, and responded to in vivo stimuli. This method of generating purified pituitary tissue opens new avenues of research for pituitary regenerative medicine.

    DOI: 10.1016/j.stemcr.2023.05.002

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  12. 高脂肪食摂取により生じる視床下部弓状核と中脳腹側被蓋野の炎症は自発運動により抑制される

    佐々木 智之, 杉山 摩利子, 久納 光皓, 孫 汝楠, 廣瀬 友矩, 高木 博史, 坂野 僚一, 有馬 寛

    日本内分泌学会雑誌   99 巻 ( 1 ) 頁: 322 - 322   2023年5月

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    記述言語:日本語   出版者・発行元:(一社)日本内分泌学会  

  13. 線条体ニューロンにおけるPTP1Bは高脂肪食に対する報酬効果を増強する

    久納 光皓, 坂野 僚一, 王 思嫻, 佐々木 智之, 孫 汝楠, 廣瀬 友矩, 杉山 摩利子, 高木 博史, 有馬 寛

    日本内分泌学会雑誌   99 巻 ( 1 ) 頁: 321 - 321   2023年5月

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    記述言語:日本語   出版者・発行元:(一社)日本内分泌学会  

  14. Generation of hypothalamic neural stem cell-like cells<i> in</i><i> vitro</i> from human pluripotent stem cells 国際誌

    Miwata, T; Suga, H; Kawaguchi, Y; Sakakibara, M; Kano, M; Taga, S; Soen, M; Ozaki, H; Asano, T; Sasaki, H; Miyata, T; Yasuda, Y; Kobayashi, T; Sugiyama, M; Onoue, T; Takagi, H; Hagiwara, D; Iwama, S; Arima, H

    STEM CELL REPORTS   18 巻 ( 4 ) 頁: 869 - 883   2023年4月

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

    When damaged, restoring the function of the hypothalamus is currently impossible. It is unclear whether neural stem cells exist in the hypothalamus. Studies have reported that adult rodent tanycytes around the third ventricle function as hypothalamic neural stem cell-like cells. However, it is currently impossible to collect periventricular cells from humans. We attempted to generate hypothalamic neural stem cell-like cells from human embryonic stem cells (ESCs). We focused on retina and anterior neural fold homeobox (RAX) because its expression is gradually restricted to tanycytes during the late embryonic stage. We differentiated RAX::VENUS knockin human ESCs (hESCs) into hypothalamic organoids and sorted RAX+ cells from mature organoids. The isolated RAX+ cells formed neurospheres and exhibited self-renewal and multipotency. Neurogenesis was observed when neurospheres were transplanted into the mouse hypothalamus. We isolated RAX+ hypothalamic neural stem cell-like cells from wild-type human ES organoids. This is the first study to differentiate human hypothalamic neural stem cell-like cells from pluripotent stem cells.

    DOI: 10.1016/j.stemcr.2023.02.006

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  15. Dapagliflozinは脂質と食塩の過剰摂取によって生じる耐糖能異常を改善する

    廣瀬 友矩, 高木 博史, 久納 光皓, 佐々木 智之, 孫 汝楠, 杉山 摩利子, 坂野 僚一, 有馬 寛

    糖尿病   66 巻 ( Suppl.1 ) 頁: S - 232   2023年4月

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    記述言語:日本語   出版者・発行元:(一社)日本糖尿病学会  

  16. Mineralocorticoids induce polyuria by reducing apical aquaporin-2 expression of the kidney in partial vasopressin deficiency.

    Kurimoto J, Takagi H, Miyata T, Kawaguchi Y, Hodai Y, Tsumura T, Hagiwara D, Kobayashi T, Yasuda Y, Sugiyama M, Onoue T, Iwama S, Suga H, Banno R, Katsuki T, Ando F, Uchida S, Arima H

    Endocrine journal   70 巻 ( 3 ) 頁: 295 - 304   2023年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:一般社団法人 日本内分泌学会  

    The symptoms of diabetes insipidus may be masked by the concurrence of adrenal insufficiency and emerge after the administration of hydrocortisone, occasionally at high doses. To elucidate the mechanism underlying polyuria induced by the administration of high-dose corticosteroids in the deficiency of arginine vasopressin (AVP), we first examined the secretion of AVP in three patients in whom polyuria was observed only after the administration of high-dose corticosteroids. Next, we examined the effects of dexamethasone or aldosterone on water balance in wild-type and familial neurohypophyseal diabetes insipidus (FNDI) model mice. A hypertonic saline test showed that AVP secretion was partially impaired in all patients. In one patient, there were no apparent changes in AVP secretion before and after the administration of high-dose corticosteroids. In FNDI mice, unlike dexamethasone, the administration of aldosterone increased urine volumes and decreased urine osmolality. Immunohistochemical analyses showed that, after the administration of aldosterone in FNDI mice, aquaporin-2 expression was decreased in the apical membrane and increased in the basolateral membrane in the collecting duct. These changes were not observed in wild-type mice. The present data suggest that treatment with mineralocorticoids induces polyuria by reducing aquaporin-2 expression in the apical membrane of the kidney in partial AVP deficiency.

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  17. Resting energy expenditure depends on energy intake during weight loss in people with obesity: a retrospective cohort study 国際誌

    Handa, T; Onoue, T; Kobayashi, T; Wada, E; Hayase, A; Kinoshita, T; Yamagami, A; Yasuda, Y; Iwama, S; Kawaguchi, Y; Miyata, T; Sugiyama, M; Takagi, H; Hagiwara, D; Suga, H; Banno, R; Goto, M; Arima, H

    ARCHIVES OF ENDOCRINOLOGY METABOLISM   67 巻 ( 2 ) 頁: 233 - 241   2023年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Archives of Endocrinology and Metabolism  

    Objective: Resting energy expenditure (REE) decreases if there is reduced energy intake and body weight (BW). The decrease in REE could make it difficult for patients with obesity to maintain decreased BW. This study aimed to investigate the correlation among changes in REE, energy intake, and BW during the weight loss process in patients with obesity. Materials and methods: We conducted a retrospective cohort study of patients hospitalized for the treatment of obesity in Japan. Patients received fully controlled diet during hospitalization and performed exercises if able. REE was measured once a week using a hand-held indirect calorimetry. Energy intake was determined by actual dietary intake. Results: Of 44 inpatients with obesity, 17 were included in the analysis. Their BW decreased significantly after 1 week (−4.7 ± 2.0 kg, P < 0.001) and 2 weeks (−5.7 ± 2.2 kg, P < 0.001). The change in REE after 1 and 2 weeks was positively correlated with the energy intake/ energy expenditure ratio (r = 0.66, P = 0.004 at 1 week, r = 0.71, P = 0.002 at 2 weeks). Using a regression equation (y = 0.5257x – 43.579), if the energy intake/energy expenditure ratio within the second week was 82.9%, the REE after 2 weeks was similar to the baseline level. There was no significant correlation between the change in REE and BW. Conclusions: Our data suggest that changes in REE depend on energy intake/energy expenditure ratio and that the decrease in REE can be minimized by matching energy intake to energy expenditure, even during the weight loss process. Arch Endocrinol Metab. 2023;67(2):233-41.

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  18. Knockdown of endoplasmic reticulum chaperone BiP leads to the death of parvocellular AVP/CRH neurons in mice 国際誌

    Kawaguchi, Y; Hagiwara, D; Tsumura, T; Miyata, T; Kobayashi, T; Sugiyama, M; Onoue, T; Yasuda, Y; Iwama, S; Suga, H; Banno, R; Grinevich, V; Arima, H

    JOURNAL OF NEUROENDOCRINOLOGY   35 巻 ( 1 ) 頁: e13223   2023年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Neuroendocrinology  

    Arginine vasopressin (AVP) is expressed in both magnocellular (magnAVP) and parvocellular AVP (parvAVP) neurons of the paraventricular nucleus, and AVP colocalizes with corticotropin-releasing hormone (CRH) only in the parvocellular neurons. The immunoglobulin heavy chain binding protein (BiP) is a major endoplasmic reticulum (ER) chaperone which regulates the unfolded protein response under ER stress. We previously demonstrated that knockdown of BiP in magnAVP neurons exacerbated ER stress, which resulted in the autophagy-associated cell death of magnAVP neurons. Using the same approach, in the present study we examined the role of BiP in mouse parvAVP/CRH neurons. Our data demonstrate that BiP is expressed in mouse parvAVP/CRH neurons under nonstress conditions and is upregulated in proportion to the increase in CRH expression after adrenalectomy. For BiP knockdown in parvAVP/CRH neurons, we utilized a viral approach in combination with shRNA interference. Knockdown of BiP expression induced ER stress in parvAVP/CRH neurons, as reflected by the expression of C/EBP homologous protein. Furthermore, BiP knockdown led to the loss of parvAVP/CRH neurons after 4 weeks. In summary, our results demonstrate that BiP plays a pivotal role in parvAVP/CRH neurons, which function as neuroendocrine cells producing a large number of secretory proteins.

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  19. Mineralocorticoids induce polyuria by reducing apical aquaporin-2 expression of the kidney in partial vasopressin deficiency

    Kurimoto Junki, Takagi Hiroshi, Miyata Takashi, Kawaguchi Yohei, Hodai Yuichi, Tsumura Tetsuro, Hagiwara Daisuke, Kobayashi Tomoko, Yasuda Yoshinori, Sugiyama Mariko, Onoue Takeshi, Iwama Shintaro, Suga Hidetaka, Banno Ryoichi, Katsuki Takeshi, Ando Fumiaki, Uchida Shinichi, Arima Hiroshi

    ENDOCRINE JOURNAL   70 巻 ( 3 ) 頁: 295 - 304   2023年

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  20. Differentiation of human induced pluripotent stem cells into hypothalamic vasopressin neurons with minimal exogenous signals and partial conversion to the naive state 国際誌

    Ozaki, H; Suga, H; Sakakibara, M; Soen, M; Miyake, N; Miwata, T; Taga, S; Nagai, T; Kano, M; Mitsumoto, K; Miyata, T; Kobayashi, T; Sugiyama, M; Onoue, T; Takagi, H; Hagiwara, D; Iwama, S; Banno, R; Iguchi, G; Takahashi, Y; Muguruma, K; Inoue, H; Arima, H

    SCIENTIFIC REPORTS   12 巻 ( 1 ) 頁: 17381 - 17381   2022年10月

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

    Familial neurohypophyseal diabetes insipidus (FNDI) is a degenerative disease of vasopressin (AVP) neurons. Studies in mouse in vivo models indicate that accumulation of mutant AVP prehormone is associated with FNDI pathology. However, studying human FNDI pathology in vivo is technically challenging. Therefore, an in vitro human model needs to be developed. When exogenous signals are minimized in the early phase of differentiation in vitro, mouse embryonic stem cells (ESCs)/induced pluripotent stem cells (iPSCs) differentiate into AVP neurons, whereas human ESCs/iPSCs die. Human ESCs/iPSCs are generally more similar to mouse epiblast stem cells (mEpiSCs) compared to mouse ESCs. In this study, we converted human FNDI-specific iPSCs by the naive conversion kit. Although the conversion was partial, we found improved cell survival under minimal exogenous signals and differentiation into rostral hypothalamic organoids. Overall, this method provides a simple and straightforward differentiation direction, which may improve the efficiency of hypothalamic differentiation.

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  21. Elevated TSH Level, TgAb, and Prior Use of Ramucirumab or TKIs as Risk Factors for Thyroid Dysfunction in PD-L1 Blockade 国際誌

    Kobayashi, T; Iwama, S; Yamagami, A; Yasuda, Y; Okuji, T; Ito, M; Zhou, X; Ando, M; Onoue, T; Miyata, T; Sugiyama, M; Hagiwara, D; Suga, H; Banno, R; Hase, T; Morise, M; Ito, T; Kikumori, T; Inoue, M; Ando, Y; Masuda, N; Kawashima, H; Hashimoto, N; Arima, H

    JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM   107 巻 ( 10 ) 頁: E4115 - E4123   2022年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Clinical Endocrinology and Metabolism  

    Background: Thyroid dysfunction is frequently caused by treatment with antiprogrammed cell death-1 ligand 1 antibodies (PD-L1-Abs) and anticancer drugs, including ramucirumab (RAM) and multitargeted tyrosine kinase inhibitors (multi-TKIs), which are often used prior to PD-L1-Ab treatment in cancer patients. Methods: A total of 148 patients treated with PD-L1-Abs were evaluated for antithyroid antibodies at baseline and for thyroid function every 6 weeks for 24 weeks after treatment initiation and then were observed until the visits stopped. Results: Of the 148 patients, 15 (10.1%) developed thyroid dysfunction after PD-L1-Ab treatment (destructive thyroiditis in 8 and hypothyroidism without preceding thyrotoxicosis in 7). The prevalence of an elevated thyroid-stimulating hormone (TSH) level at baseline (3/15 [20.0%] vs 4/133 [3.0%], P < .05), positive antithyroglobulin antibodies (TgAbs) at baseline (4/15 [26.7%] vs 5/133 [3.8%], P < .05) and prior treatment with RAM or multi-TKIs (3/15 [20.0%] vs 5/133 [3.8%], P < .05) were significantly higher in patients with vs without thyroid dysfunction. In a multivariate analysis, elevated TSH level at baseline, TgAb positivity at baseline, and prior treatment with RAM or multi-TKIs were significantly associated with the development of thyroid dysfunction, with ORs of 7.098 (95% CI 1.154-43.638), 11.927 (95% CI 2.526-56.316), and 8.476 (95% CI 1.592-45.115), respectively. Conclusion: The results of this real-world study suggest that the risk of thyroid dysfunction induced by PD-L1-Abs can be predicted by the TSH level at baseline, TgAb positivity at baseline, and prior treatment with RAM or multi-TKIs.

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  22. Inflammation in VTA Caused by HFD Induces Activation of Dopaminergic Neurons Accompanied by Binge-like Eating 国際誌

    Sun, RN; Sugiyama, M; Wang, SX; Kuno, M; Sasaki, T; Hirose, T; Miyata, T; Kobayashi, T; Tsunekawa, T; Onoue, T; Yasuda, Y; Takagi, H; Hagiwara, D; Iwama, S; Suga, H; Arima, H

    NUTRIENTS   14 巻 ( 18 )   2022年9月

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

    Binge eating is a characteristic symptom observed in obese individuals that is related to dysfunction of dopaminergic neurons (DNs). Intermittent administration of a high-fat diet (HFD) is reported to induce binge-like eating, but the underlying mechanisms remain unclear. We generated dopaminergic neuron specific IKKβ deficient mice (KO) to examine the effects of inflammation in DNs on binge-like eating under inflammatory conditions associated with HFD. After administration of HFD for 4 weeks, mice were fasted for 24 h, and then the consumption of HFD was measured for 2 h. We also evaluated that the mRNA expressions of inflammatory cytokines, glial markers, and dopamine signaling-related genes in the ventral tegmental area (VTA) and striatum. Moreover, insulin was administered intraventricularly to assess downstream signaling. The consumption of HFD was significantly reduced, and the phosphorylation of AKT in the VTA was significantly increased in female KO compared to wild-type (WT) mice. Analyses of mRNA expressions revealed that DNs activity and inflammation in the VTA were significantly decreased in female KO mice. Thus, our data suggest that HFD-induced inflammation with glial cell activation in the VTA affects DNs function and causes abnormal eating behaviors accompanied by insulin resistance in the VTA of female mice.

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  23. Protein Tyrosine Phosphatase 1B Deficiency Improves Glucose Homeostasis in Type 1 Diabetes Treated With Leptin 国際誌

    Ito, Y; Sun, R; Yagimuma, H; Taki, K; Mizoguchi, A; Kobayashi, T; Sugiyama, M; Onoue, T; Tsunekawa, T; Takagi, H; Hagiwara, D; Iwama, S; Suga, H; Konishi, H; Kiyama, H; Arima, H; Banno, R

    DIABETES   71 巻 ( 9 ) 頁: 1902 - 1914   2022年9月

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

    Leptin, a hormone secreted by adipocytes, exhibits therapeutic potential for the treatment of type 1 diabetes (T1D). Protein tyrosine phosphatase 1B (PTP1B) is a key enzyme that negatively regulates leptin receptor signaling. Here, the role of PTP1B in the treatment of T1D was investigated using PTP1B-deficient (knockout [KO]) mice and a PTP1B inhibitor. T1D wild-type (WT) mice induced by streptozotocin showed marked hyperglycemia compared with nonT1D WT mice. KO mice displayed significantly improved glucose metabolism equivalent to non-T1D WT mice, whereas peripheral or central administration of leptin partially improved glucose metabolism in T1D WT mice. Peripheral combination therapy of leptin and a PTP1B inhibitor in T1D WT mice improved glucose metabolism to the same level as non-T1D WT mice. Leptin was shown to act on the arcuate nucleus in the hypothalamus to suppress gluconeogenesis in liver and enhance glucose uptake in both brown adipose tissue and soleus muscle through the sympathetic nervous system. These effects were enhanced by PTP1B deficiency. Thus, treatment of T1D with leptin, PTP1B deficiency, or a PTP1B inhibitor was shown to enhance leptin activity in the hypothalamus to improve glucose metabolism. These findings suggest a potential alternative therapy for T1D.

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

    Iwama, S; Kobayashi, T; Yasuda, Y; Okuji, T; Ito, M; Ando, M; Zhou, X; Yamagami, A; Onoue, T; Kawaguchi, Y; Miyata, T; Sugiyama, M; Takagi, H; Hagiwara, D; Suga, H; Banno, R; Hase, T; Morise, M; Wakahara, K; Yokota, K; Kato, M; Nishio, N; Tanaka, C; Miyata, K; Ogura, A; Ito, T; Sawada, T; Shimokata, T; Niimi, K; Ohka, F; Ishigami, M; Gotoh, M; Hashimoto, N; Saito, R; Kiyoi, H; Kajiyama, H; Ando, Y; Hibi, H; Sone, M; Akiyama, M; Kodera, Y; Arima, H

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

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Clinical Endocrinology and Metabolism  

    Background: Previous studies showed that although the risk of thyroid dysfunction [thyroid immune-related adverse events (irAEs)] induced by anti-programmed cell death-1 antibodies (PD-1-Ab) was as low as 2% to 7% in patients negative for anti-thyroid antibodies (ATAs) at baseline, it was much higher (30%-50%) in patients positive for ATAs. However, whether a similar increase occurs with combination therapy using PD-1-Ab plus anti-cytotoxic T-lymphocyte antigen-4 antibody (CTLA-4-Ab) is unknown. Methods: A total of 451 patients with malignancies treated with PD-1-Ab, CTLA-4-Ab, or a combination of PD-1-Ab and CTLA-4-Ab (PD-1/CTLA-4-Abs) were evaluated for ATAs at baseline and for thyroid function every 6 weeks for 24 weeks after treatment initiation and then observed until the last clinical visit. Results: Of the 451 patients, 51 developed thyroid irAEs after immunotherapy [41 of 416 (9.9%) treated with PD-1-Ab, 0 of 8 (0%) treated with CTLA-4-Ab, and 10 of 27 (37.0%) treated with PD-1/CTLA-4-Abs]. The cumulative incidence of thyroid irAEs was significantly higher in patients who were positive vs negative for ATAs at baseline after both PD-1-Ab [28/87 (32.2%) vs 13/329 (4.0%), P < 0.001] and PD-1/CTLA-4-Abs [6/10 (60.0%) vs 4/17 (23.5%), P < 0.05] treatments. The risk of thyroid irAEs induced by PD-1/CTLA-4Abs, which was significantly higher than that induced by PD-1-Ab, in patients negative for ATAs at baseline was not statistically different from that induced by PD-1-Ab in patients positive for ATAs at baseline. Conclusions: This study showed that the incidence of thyroid irAEs was high and not negligible after PD-1/CTLA-4-Abs treatment even in patients negative for ATAs at baseline.

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  25. Functional Lactotrophs in Induced Adenohypophysis Differentiated From Human iPS Cells 査読有り 国際誌

    Miyake, N; Nagai, T; Suga, H; Osuka, S; Kasai, T; Sakakibara, M; Soen, M; Ozaki, H; Miwata, T; Asano, T; Kano, M; Muraoka, A; Nakanishi, N; Nakamura, T; Goto, M; Yasuda, Y; Kawaguchi, Y; Miyata, T; Kobayashi, T; Sugiyama, M; Onoue, T; Hagiwara, D; Iwama, S; Iwase, A; Inoshita, N; Arima, H; Kajiyama, H

    ENDOCRINOLOGY   163 巻 ( 3 )   2022年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   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.

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  26. 高脂肪食摂取に伴う中脳腹側被蓋野の炎症は絶食後の摂餌量を増加させる

    孫 汝楠, 杉山 摩利子, 佐々木 智之, 廣瀬 友矩, 恒川 卓, 高木 博史, 坂野 僚一, 有馬 寛

    肥満研究   27 巻 ( Suppl. ) 頁: 342 - 342   2022年3月

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    記述言語:日本語   出版者・発行元:(一社)日本肥満学会  

  27. 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] 国際誌

    Wada, E; Onoue, T; Kinoshita, T; Hayase, A; Handa, T; Ito, M; Furukawa, M; Okuji, T; Kobayashi, T; Iwama, S; Sugiyama, M; Takagi, H; Hagiwara, D; Suga, H; Banno, R; Goto, M; Arima, H

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

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    記述言語:英語   出版者・発行元:Diabetologia  

    DOI: 10.1007/s00125-021-05610-4

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

    Wada, E; Onoue, T; Kinoshita, T; Hayase, A; Handa, T; Ito, M; Furukawa, M; Okuji, T; Kobayashi, T; Iwama, S; Sugiyama, M; Takagi, H; Hagiwara, D; Suga, H; Banno, R; Goto, M; Arima, H

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

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   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.]

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  29. GABA<sub>B</sub> receptor signaling in the caudate putamen is involved in binge-like consumption during a high fat diet in mice 国際誌

    Sun, RN; Tsunekawa, T; Hirose, T; Yaginuma, H; Taki, K; Mizoguchi, A; Miyata, T; Kobayashi, T; Sugiyama, M; Onoue, T; Takagi, H; Hagiwara, D; Ito, Y; Iwama, S; Suga, H; Banno, R; Bettler, B; Arima, H

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

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   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.

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

    Kurimoto, J; Takagi, H; Miyata, T; Hodai, Y; Kawaguchi, Y; Hagiwara, D; Suga, H; Kobayashi, T; Sugiyama, M; Onoue, T; Ito, Y; Iwama, S; Banno, R; Tanabe, K; Tanizawa, Y; Arima, H

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

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    記述言語:英語   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.

    DOI: 10.1007/s11102-021-01135-6

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

    Mizoguchi, A; Banno, R; Sun, R; Yaginuma, H; Taki, K; Kobayashi, T; Sugiyama, M; Tsunekawa, T; Onoue, T; Takagi, H; Hagiwara, D; Ito, Y; Iwama, S; Suga, H; Nagai, T; Yamada, K; Arima, H

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

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   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.

    DOI: 10.1038/s41598-021-92386-7

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  32. CD4<SUP>+</SUP> T cells are essential for the development of destructive thyroiditis induced by anti-PD-1 antibody in thyroglobulin-immunized mice 国際誌

    Yasuda, Y; Iwama, S; Sugiyama, D; Okuji, T; Kobayashi, T; Ito, M; Okada, N; Enomoto, A; Ito, S; Yan, Y; Sugiyama, M; Onoue, T; Tsunekawa, T; Ito, Y; Takagi, H; Hagiwara, D; Goto, M; Suga, H; Banno, R; Takahashi, M; Nishikawa, H; Arima, H

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

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    記述言語:英語   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.

    DOI: 10.1126/scitranslmed.abb7495

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

    Mizoguchi, A; Banno, R; Sun, RN; Yaginuma, H; Taki, K; Kobayashi, T; Sugiyama, M; Tsunekawa, T; Onoue, T; Takagi, H; Hagiwara, D; Ito, Y; Iwama, S; Suga, H; Arima, H

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

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    記述言語:英語   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.

    DOI: 10.1016/j.neuroscience.2021.02.009

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

    Hagiwara, D; Tochiya, M; Azuma, Y; Tsumura, T; Hodai, Y; Kawaguchi, Y; Miyata, T; Kobayashi, T; Sugiyama, M; Onoue, T; Takagi, H; Ito, Y; Iwama, S; Suga, H; Banno, R; Arima, H

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

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    記述言語:英語   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.

    DOI: 10.1016/j.peptides.2021.170517

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

    Kobayashi, T; Iwama, S; Sugiyama, D; Yasuda, Y; Okuji, T; Ito, M; Ito, S; Sugiyama, M; Onoue, T; Takagi, H; Hagiwara, D; Ito, Y; Suga, H; Banno, R; Nishikawa, H; Arima, H

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

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    記述言語:英語   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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  36. 食塩過剰摂取は高脂肪食によって惹起される膵β細胞増殖を抑制して耐糖能を悪化させる

    滝 啓吾, 高木 博史, 廣瀬 友矩, 孫 汝楠, 柳沼 裕史, 杉山 摩利子, 伊藤 禎浩, 坂野 僚一, 有馬 寛

    日本内分泌学会雑誌   97 巻 ( 1 ) 頁: 321 - 321   2021年4月

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    記述言語:日本語   出版者・発行元:(一社)日本内分泌学会  

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

    Taki, K; Takagi, H; Hirose, T; Sun, RN; Yaginuma, H; Mizoguchi, A; Kobayashi, T; Sugiyama, M; Tsunekawa, T; Onoue, T; Hagiwara, D; Ito, Y; Iwama, S; Suga, H; Banno, R; Sakano, D; Kume, S; Arima, H

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

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    記述言語:英語   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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  38. 胆管癌に伴う閉塞性黄疸の解除後、約3ヵ月でインスリン離脱となった1例

    木下 珠希, 杉山 摩利子, 有馬 寛

    糖尿病   64 巻 ( 2 ) 頁: 151 - 151   2021年2月

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    記述言語:日本語   出版者・発行元:(一社)日本糖尿病学会  

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

    Yaginuma, H; Banno, R; Sun, R; Taki, K; Mizoguchi, A; Kobayashi, T; Sugiyama, M; Tsunekawa, T; Onoue, T; Takagi, H; Hagiwara, D; Ito, Y; Iwama, S; Suga, H; Arima, H

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

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   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.

    DOI: 10.1016/j.jphs.2021.08.010

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

    Kawaguchi, Y; Hagiwara, D; Miyata, T; Hodai, Y; Kurimoto, J; Takagi, H; Suga, H; Kobayashi, T; Sugiyama, M; Onoue, T; Ito, Y; Iwama, S; Banno, R; Grinevich, V; Arima, H

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

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    記述言語:英語   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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  41. Degradation of Mutant Protein Aggregates within the Endoplasmic Reticulum of Vasopressin Neurons 国際誌

    Miyata, T; Hagiwara, D; Hodai, Y; Miwata, T; Kawaguchi, Y; Kurimoto, J; Ozaki, H; Mitsumoto, K; Takagi, H; Suga, H; Kobayashi, T; Sugiyama, M; Onoue, T; Ito, Y; Iwama, S; Banno, R; Matsumoto, M; Kawakami, N; Ohno, N; Sakamoto, H; Arima, H

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

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    記述言語:英語   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.

    DOI: 10.1016/j.isci.2020.101648

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  42. 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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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  43. 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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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  44. 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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  45. インスリン依存性糖尿病モデルマウスの糖代謝はインスリン非投与下でレプチンおよびSGLT2阻害剤の併用投与により改善する

    柳沼 裕史, 坂野 僚一, 孫 汝楠, 滝 啓吾, 杉山 摩利子, 恒川 卓, 高木 博史, 伊藤 禎浩, 有馬 寛

    糖尿病   63 巻 ( Suppl.1 ) 頁: S - 199   2020年8月

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    記述言語:日本語   出版者・発行元:(一社)日本糖尿病学会  

  46. 高脂肪食負荷マウスにおいて食塩過剰摂取はインスリン分泌低下を介して耐糖能を悪化させる

    滝 啓吾, 高木 博史, 孫 汝楠, 柳沼 裕史, 杉山 摩利子, 恒川 卓, 伊藤 禎浩, 坂野 僚一, 有馬 寛

    糖尿病   63 巻 ( Suppl.1 ) 頁: S - 131   2020年8月

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    記述言語:日本語   出版者・発行元:(一社)日本糖尿病学会  

  47. 報酬系による糖代謝調節機構の解明 GABAB受容体ノックアウトマウスを用いた検討

    恒川 卓, 坂野 僚一, 孫 汝楠, 柳沼 裕史, 滝 啓吾, 杉山 摩利子, 高木 博史, 伊藤 禎浩, 有馬 寛

    糖尿病   63 巻 ( Suppl.1 ) 頁: S - 111   2020年8月

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    記述言語:日本語   出版者・発行元:(一社)日本糖尿病学会  

  48. タモキシフェン誘導性Creマウスを用いたアストロサイト特異的PTP1B欠損マウスの表現型解析

    杉山 摩利子, 坂野 僚一, 孫 汝楠, 柳沼 裕史, 滝 啓吾, 恒川 卓, 高木 博史, 伊藤 禎浩, 有馬 寛

    日本内分泌学会雑誌   96 巻 ( 1 ) 頁: 352 - 352   2020年8月

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  49. 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, M; Banno, R; Yaginuma, H; Taki, K; Mizoguchi, A; Tsunekawa, T; Onoue, T; Takagi, H; Ito, Y; Iwama, S; Goto, M; Suga, H; Komine, O; Yamanaka, K; Arima, H

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

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    記述言語:英語   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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  50. 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, N; Iwama, S; Okuji, T; Kobayashi, T; Yasuda, Y; Wada, E; Onoue, T; Goto, M; Sugiyama, M; Tsunekawa, T; Takagi, H; Hagiwara, D; Ito, Y; Suga, H; Banno, R; Hase, T; Morise, M; Kanda, M; Yokota, K; Hashimoto, N; Ando, M; Fujimoto, Y; Nagino, M; Kodera, Y; Fujishiro, M; Hibi, H; Sone, M; Kiyoi, H; Gotoh, M; Ando, Y; Akiyama, M; Hasegawa, Y; Arima, H

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

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    記述言語:英語   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.

    DOI: 10.1038/s41416-020-0736-7

    Web of Science

    Scopus

    PubMed

  51. 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, E; Onoue, T; Kobayashi, T; Handa, T; Hayase, A; Ito, M; Furukawa, M; Okuji, T; Okada, N; Iwama, S; Sugiyama, M; Tsunekawa, T; Takagi, H; Hagiwara, D; Ito, Y; Suga, H; Banno, R; Kuwatsuka, Y; Ando, M; Goto, M; Arima, H

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

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    記述言語:英語   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

    Scopus

    PubMed

  52. 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, T; Iwama, S; Yasuda, Y; Okada, N; Okuji, T; Ito, M; Onoue, T; Goto, M; Sugiyama, M; Tsunekawa, T; Takagi, H; Hagiwara, D; Ito, Y; Suga, H; Banno, R; Yokota, K; Hase, T; Morise, M; Hashimoto, N; Ando, M; Fujimoto, Y; Hibi, H; Sone, M; Ando, Y; Akiyama, M; Hasegawa, Y; Arima, H

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

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    記述言語:英語   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

    Web of Science

    Scopus

    PubMed

  53. 高脂肪食の継続投与はグリア細胞の極性変化を伴い視床下部炎症が増悪する

    杉山 摩利子, 坂野 僚一, 柳沼 裕史, 滝 啓吾, 溝口 暁, 恒川 卓, 高木 博史, 伊藤 禎浩, 小峯 起, 山中 宏二, 有馬 寛

    肥満研究   24 巻 ( Suppl. ) 頁: 185 - 185   2018年9月

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    記述言語:日本語   出版者・発行元:(一社)日本肥満学会  

▼全件表示

書籍等出版物 2

  1. 【神経が司る 代謝・炎症制御と生体恒常性 臓器ネットワークを理解し、疾患予防・治療へ繋ぐ】(第1章)神経による代謝調節 神経系を介した遠心性代謝制御 レプチンによる糖代謝調節機構

    坂野僚一( 担当: 共著)

    羊土社  2023年12月 

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    総ページ数:7   担当ページ:7   記述言語:日本語 著書種別:教科書・概説・概論

  2. 内分泌代謝・糖尿病内科領域の新専門医制度

    槙田紀子( 担当: 共著)

    科学評論社  2023年3月 

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    総ページ数:6   担当ページ:6   記述言語:日本語 著書種別:教科書・概説・概論

MISC 1

  1. 出産を契機に橋本病からバセドウ病に転じた1例

    安田 康紀, 岩間 信太郎, 川久保 充裕, 杉山 摩利子, 岩田 尚子, 尾方 秀忠, 片平 正人, 椙村 益久, 有馬 寛  

    日本内分泌学会雑誌92 巻 ( 3 ) 頁: 621 - 621   2017年1月

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    記述言語:日本語   出版者・発行元:(一社)日本内分泌学会  

    J-GLOBAL

講演・口頭発表等 16

  1. Voluntary wheel running improves a high-fat diet-induced inflammation and insulin resistance in hypothalamic arcuate nucleus and ventral tegmental area in male mice 国際会議

    Sasaki T, Sugiyama M, Kuno M, Takagi H, Banno R, Arima H

    2024年3月 

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    開催年月日: 2024年3月

  2. セマグルチドの短期・長期投与は脳内報酬系の活動を抑制し、高脂肪食の過剰摂取を抑制する

    武田理、近藤邦生、杉山摩利子、有馬寛、箕越靖彦

    第37回日本糖尿病・肥満動物学会年次学術集会  2024年3月 

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    開催年月日: 2024年3月

  3. セマグルチドは高脂肪食摂取に関連する脳内報酬系の活動を選択的に抑制する

    武田理、近藤邦生、杉山摩利子、有馬寛、箕越靖彦

    第8回食欲・食嗜好を形成する感覚・内分泌・神経基盤研究会  2024年1月 

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    開催年月日: 2024年1月

  4. 報酬系ニューロンにおけるPTP1B欠損は高脂肪食の過剰摂取を抑制する

    久納光皓、坂野僚一、佐々木智之、杉山摩利子、髙木博史、有馬寛

    第44回日本肥満学会  2023年11月 

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    開催年月日: 2023年11月

  5. 自発運動は高脂肪食摂取に伴う脳内のインスリン抵抗性を改善する

    佐々木智之、杉山摩利子、久納光皓、高木博史、坂野僚一、有馬寛

    第44回日本肥満学会  2023年11月 

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    開催年月日: 2023年11月

  6. セマグルチドは高脂肪食摂取に関連する脳内報酬系の活動を抑制する

    武田理、近藤邦生、杉山摩利子、有馬寛、箕越靖彦

    第44回日本肥満学会  2023年11月 

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    開催年月日: 2023年11月

    記述言語:日本語   会議種別:口頭発表(一般)  

  7. パシレオチドによりインスリン分泌が枯渇し血糖管理に苦慮したクッシング病の一例

    尾崎 緑、杉山 摩利子、萩原 大輔、坂野 僚一、有馬 寛

    第97回日本糖尿病学会中部地方会  2023年9月 

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    開催年月日: 2023年9月

  8. 減量術前後に基礎代謝、体組成の変化を観察し得た2型糖尿病合併高度肥満症の1例

    石黒文菜、杉山摩利子、前田龍太郎、久納光皓、佐々木智之、半田朋子、小林朋子、尾上剛史、萩原大輔、坂野僚一、有馬寛

    第97回日本糖尿病学会中部地方会  2023年9月 

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    開催年月日: 2023年9月

  9. 高脂肪食摂取に伴う脳内炎症がエネルギー代謝に与える影響について 招待有り

    杉山 摩利子、坂野 僚一、有馬 寛

    第96回日本内分泌学会学術総会  2023年6月 

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    開催年月日: 2023年6月

    記述言語:日本語   会議種別:シンポジウム・ワークショップ パネル(指名)  

  10. 線条体ニューロンにおけるPTP1Bは高脂肪食に対する報酬効果を増強する

    久納光皓、坂野僚一、王思嫻、佐々木智之、孫汝楠、廣瀬友矩、杉山摩利子、髙木博史、有馬寛

    第96回日本内分泌学会学術総会  2023年6月 

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    開催年月日: 2023年6月

  11. 高脂肪食摂取により生じる視床下部弓状核と中脳腹側被蓋野の炎症は自発運動により抑制される

    佐々木智之、杉山摩利子、久納光皓、孫汝楠、廣瀬友矩、高木博史、坂野僚一、有馬寛

    第96回日本内分泌学会学術総会  2023年6月 

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    開催年月日: 2023年6月

  12. Dapagliflozinは脂質と食塩の過剰摂取によって生じる耐糖能異常を改善する

    廣瀬友矩、髙木博史、久納光皓、佐々木智之、孫汝楠、杉山摩利子、坂野僚一、有馬寛

    第66回日本糖尿病学会年次学術集会  2023年5月 

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    開催年月日: 2023年5月

  13. 高脂肪食摂取に伴う中脳腹側被蓋野の炎症によりドーパミンシグナルが活性化され過食が生じる

    孫汝楠, 杉山摩利子, 久納光皓, 王思嫻, 佐々木智之, 廣瀬友矩, 恒川卓, 髙木博史, 坂野僚一, 有馬寛

    第43回日本肥満学会  2022年12月 

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    開催年月日: 2022年12月

    記述言語:日本語   会議種別:口頭発表(一般)  

  14. Dapagliflozinは脂質と食塩の過剰摂取によって生じる耐糖能異常を改善する 招待有り

    髙木博史, 廣瀬友矩, 久納光皓, 佐々木智之, 孫汝楠, 杉山 摩利子, 坂野僚一, 有馬寛

    大学共同利用機関法人 自然科学研究機構 生理学研究所 研究会「運動器/代謝系連関による生体機能制御とその変容の仕組み」  2022年11月 

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    開催年月日: 2022年11月

    記述言語:日本語   会議種別:口頭発表(招待・特別)  

  15. Inflammation in VTA induced by HFD activates dopaminergic neurons leading to overeating 国際会議

    R. Sun, M. Sugiyama, M. Kuno, S. Ou, T. Sasaki, T. Hirose, T. Tsunekawa, H. Takagi, R. Banno, and H. Arima

    ObesityWeek 2022  2022年11月 

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    開催年月日: 2022年11月

    記述言語:英語   会議種別:ポスター発表  

    開催地:USA  

  16. 中脳腹側被蓋野ドーパミンニューロンにおけるPTP1Bは高脂肪食に対する報酬効果を増強する

    王思嫻, 坂野僚一, 苟楊, 劉氷陽, 孫汝楠, 佐々木智之, 廣瀬友矩, 杉山摩利子, 有馬寛, 小池晃彦

    第95回日本内分泌学会学術総会  2022年6月 

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    開催年月日: 2022年6月

    記述言語:日本語   会議種別:ポスター発表  

▼全件表示

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 

      詳細を見る

    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

    日本学術振興会  科学研究費助成事業  若手研究

    杉山 摩利子

      詳細を見る

    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。
    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、その結果炎症が惹起され、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ことが示唆されているが、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、運動負荷が脳内炎症に与える影響を検討した。自発運動をHFD摂取と同時に開始すると、体重は増加せず、視床下部および中脳腹側被害野の炎症が減弱した。自発運動は脳内炎症の減弱を介してエネルギー代謝を改善する可能性が示唆された。
    日本肥満学会では、運動療法が減量体重の維持、肥満予防に有用であることをGrade Aで推奨している。日常の自発的な身体活動は消費されるエネルギー量は少ないものの様々な論文のメタ解析から減量に有用であることが報告されている。研究代表者は自発運動によるエネルギー消費とは別に、自発運動が中枢に影響を与えエネルギーバランスの調節機構に関与すると仮説を立てて検証し、自発運動は高脂肪食摂取に伴う脳内炎症がグリア細胞を介して抑制される可能性を見出した。本研究成果により得られた知見は継続的に実践可能な運動処方の開発に寄与しグリア細胞に与える分子機序の解明により新たな創薬開発の一助となる可能性を秘めている。

  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

    日本学術振興会  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。

 

担当経験のある科目 (本学) 1

  1. 内科 糖尿病・内分泌内科学

    2023