研究者データベース

戸田 知得(トダ チトク)
獣医学研究院 獣医学部門 基礎獣医科学分野
助教

基本情報

所属

  • 獣医学研究院 獣医学部門 基礎獣医科学分野

職名

  • 助教

学位

  • 博士(総合研究大学院大学)

J-Global ID

研究キーワード

  • 恒常性   代謝   グルコースセンシング   肥満   糖尿病   視床下部   

研究分野

  • ライフサイエンス / 生理学
  • ライフサイエンス / 代謝、内分泌学

職歴

  • 2016年11月 - 現在 北海道大学 獣医学部 助教
  • 2012年10月 - 2016年10月 イェール大学 医学部 ポスドク
  • 2009年10月 - 2012年09月 生理学研究所 生殖・内分泌系発達機構研究部門 研究員

学歴

  • 2006年04月 - 2009年09月   総合研究大学院大学   生命科学研究科   生理科学専攻
  • 2000年04月 - 2006年03月   北海道大学   獣医学部

研究活動情報

論文

  • Ming-Liang Lee, Hirokazu Matsunaga, Yuki Sugiura, Takahiro Hayasaka, Izumi Yamamoto, Taiga Ishimoto, Daigo Imoto, Makoto Suematsu, Norifumi Iijima, Kazuhiro Kimura, Sabrina Diano, Chitoku Toda
    Nature Communications 12 1 2021年12月 
    AbstractThe hypothalamus plays a central role in monitoring and regulating systemic glucose metabolism. The brain is enriched with phospholipids containing poly-unsaturated fatty acids, which are biologically active in physiological regulation. Here, we show that intraperitoneal glucose injection induces changes in hypothalamic distribution and amounts of phospholipids, especially arachidonic-acid-containing phospholipids, that are then metabolized to produce prostaglandins. Knockdown of cytosolic phospholipase A2 (cPLA2), a key enzyme for generating arachidonic acid from phospholipids, in the hypothalamic ventromedial nucleus (VMH), lowers insulin sensitivity in muscles during regular chow diet (RCD) feeding. Conversely, the down-regulation of glucose metabolism by high fat diet (HFD) feeding is improved by knockdown of cPLA2 in the VMH through changing hepatic insulin sensitivity and hypothalamic inflammation. Our data suggest that cPLA2-mediated hypothalamic phospholipid metabolism is critical for controlling systemic glucose metabolism during RCD, while continuous activation of the same pathway to produce prostaglandins during HFD deteriorates glucose metabolism.
  • Shiki Okamoto, Tatsuya Sato, Michihiro Tateyama, Haruaki Kageyama, Yuko Maejima, Masanori Nakata, Satoshi Hirako, Takashi Matsuo, Sanda Kyaw, Tetsuya Shiuchi, Chitoku Toda, Udval Sedbazar, Kumiko Saito, Nur Farehan Asgar, Boyang Zhang, Shigefumi Yokota, Kenta Kobayashi, Fabienne Foufelle, Pascal Ferré, Masamitsu Nakazato, Hiroaki Masuzaki, Seiji Shioda, Toshihiko Yada, Barbara B Kahn, Yasuhiko Minokoshi
    Cell reports 22 3 706 - 721 2018年01月16日 [査読有り][通常論文]
     
    Food selection is essential for metabolic homeostasis and is influenced by nutritional state, food palatability, and social factors such as stress. However, the mechanism responsible for selection between a high-carbohydrate diet (HCD) and a high-fat diet (HFD) remains unknown. Here, we show that activation of a subset of corticotropin-releasing hormone (CRH)-positive neurons in the rostral region of the paraventricular hypothalamus (PVH) induces selection of an HCD over an HFD in mice during refeeding after fasting, resulting in a rapid recovery from the change in ketone metabolism. These neurons manifest activation of AMP-activated protein kinase (AMPK) during food deprivation, and this activation is necessary and sufficient for selection of an HCD over an HFD. Furthermore, this effect is mediated by carnitine palmitoyltransferase 1c (CPT1c). Thus, our results identify the specific neurons and intracellular signaling pathway responsible for regulation of the complex behavior of selection between an HCD and an HFD. VIDEO ABSTRACT.
  • Shiuchi T, Toda C, Okamoto S, Coutinho EA, Saito K, Miura S, Ezaki O, Minokoshi Y
    Scientific reports 7 1 15141  2017年11月 [査読有り][通常論文]
     
    Leptin increases glucose uptake and fatty acid oxidation (FAO) in red-type skeletal muscle. However, the mechanism remains unknown. We have investigated the role of beta(2)-adrenergic receptor (AR), the major beta-AR isoform in skeletal muscle, and AMPK in leptin-induced muscle glucose uptake of mice. Leptin injection into the ventromedial hypothalamus (VMH) increased 2-deoxy-D-glucose (2DG) uptake in red-type skeletal muscle in wild-type (WT) mice accompanied with increased phosphorylation of the insulin receptor (IR) and Akt as well as of norepinephrine (NE) turnover in the muscle. Leptin-induced 2DG uptake was not observed in beta-AR-deficient (beta-less) mice despite that AMPK phosphorylation was increased in the muscle. Forced expression of beta(2)-AR in the unilateral hind limb of beta-less mice restored leptin-induced glucose uptake and enhancement of insulin signalling in red-type skeletal muscle. Leptin increased 2DG uptake and enhanced insulin signalling in red-type skeletal muscle of mice expressing a dominant negative form of AMPK (DN-AMPK) in skeletal muscle. Thus, leptin increases glucose uptake and enhances insulin signalling in red-type skeletal muscle via activation of sympathetic nerves and beta(2)-AR in muscle and in a manner independent of muscle AMPK.
  • Jung Dae Kim, Chitoku Toda, Cristina M. Ramirez, Carlos Fernandez-Hernando, Sabrina Diano
    DIABETES 66 8 2102 - 2111 2017年08月 [査読有り][通常論文]
     
    The Lin28a/Let-7 axis has been studied in peripheral tissues for its role in metabolism regulation. However, its central function remains unclear. Here we found that Lin28a is highly expressed in the hypothalamus compared with peripheral tissues. Its expression is positively correlated with positive energy balance, suggesting a potential central role for Lin28a in metabolism regulation. Thus, we targeted the hypothalamic ventromedial nucleus (VMH) to selectively overexpress (Lin28aKI(VMH)) or downregulate (Lin28aKD(VMH)) Lin28a expression in mice. With mice on a standard chow diet, body weight and glucose homeostasis were not affected in Lin28aKI(VMH) or Lin28aKD(VMH) mice. On a high-fat diet, although no differences in body weight and composition were observed, Lin28aKI(VMH) mice showed improved glucose tolerance and insulin sensitivity compared with controls. Conversely, Lin28aKD(VMH) mice displayed glucose intolerance and insulin resistance. Changes in VMH AKT activation of diet-induced obese Lin28aKI(VMH) or Lin28aKD(VMH) mice were not associated with alterations in Let-7 levels or insulin receptor activation. Rather, we observed altered expression of TANK-binding kinase-1 (TBK-1), which was found to be a direct Lin28a target mRNA. VMH-specific inhibition of TBK-1 in mice with diet-induced obesity impaired glucose metabolism and AKT activation. Altogether, our data show a TBK-1-dependent role for central Lin28a in glucose homeostasis.
  • Chitoku Toda, Anna Santoro, Jung Dae Kim, Sabrina Diano
    ANNUAL REVIEW OF PHYSIOLOGY, VOL 79 79 209 - 236 2017年 [査読有り][通常論文]
     
    The hypothalamus is an evolutionarily conserved brain structure that regulates an organism's basic functions, such as homeostasis and reproduction. Several hypothalamic nuclei and neuronal circuits have been the focus of many studies seeking to understand their role in regulating these basic functions. Within the hypothalamic neuronal populations, the arcuate melanocortin system plays a major role in controlling homeostatic functions. The arcuate pro-opiomelanocortin (POMC) neurons in particular have been shown to be critical regulators of metabolism and reproduction because of their projections to several brain areas both in and outside of the hypothalamus, such as autonomic regions of the brain stem and spinal cord. Here, we review and discuss the current understanding of POMC neurons from their development and intracellular regulators to their physiological functions and pathological dysregulation.
  • Chitoku Toda, Jung Dae Kim, Daniela Impellizzeri, Salvatore Cuzzocrea, Zhong-Wu Liu, Sabrina Diano
    CELL 164 5 872 - 883 2016年02月 [査読有り][通常論文]
     
    The ventromedial nucleus of the hypothalamus (VMH) plays a critical role in regulating systemic glucose homeostasis. How neurons in this brain area adapt to the changing metabolic environment to regulate circulating glucose levels is ill defined. Here, we show that glucose load results in mitochondrial fission and reduced reactive oxygen species in VMH neurons mediated by dynamin-related peptide 1 (DRP1) under the control of uncoupling protein 2 (UCP2). Probed by genetic manipulations and chemical-genetic control of VMH neuronal circuitry, we unmasked that this mitochondrial adaptation determines the size of the pool of glucose-excited neurons in the VMH and that this process regulates systemic glucose homeostasis. Thus, our data unmasked a critical cellular biological process controlled by mitochondrial dynamics in VMH regulation of systemic glucose homeostasis.
  • Eun Young Lee, Kenichi Sakurai, Xilin Zhang, Chitoku Toda, Tomoaki Tanaka, Meizi Jiang, Takuji Shirasawa, Kaori Tachibana, Koutaro Yokote, Antonio Vidal-Puig, Yasuhiko Minokoshi, Takashi Miki
    SCIENTIFIC REPORTS 5 17565  2015年11月 [査読有り][通常論文]
     
    High-fat diet (HFD) triggers insulin resistance and diabetes mellitus, but their link remains unclear. Characterization of overt hyperglycemia in insulin receptor mutant (Insr(P1195L/+)) mice exposed to HFD (Insr(P1195L/+)/HFD mice) revealed increased glucose-6-phosphatase (G6pc) expression in liver and increased gluconeogenesis from glycerol. Lipolysis in white adipose tissues (WAT) and lipolysis-induced blood glucose rise were increased in Insr(P1195L/+)/HFD mice, while wild-type WAT transplantation ameliorated the hyperglycemia and the increased G6pc expression. We found that the expressions of genes involved in bile acid (BA) metabolism were altered in Insr(P1195L/+)/HFD liver. Among these, the expression of Cyp7a1, a BA synthesis enzyme, was insulin-dependent and was markedly decreased in Insr(P1195L/+)/HFD liver. Reduced Cyp7 alpha 1 expression in Insr(P1195L/+)/HFD liver was rescued by WAT transplantation, and the expression of Cyp7 alpha 1 was suppressed by glycerol administration in wild-type liver. These findings suggest that unsuppressed lipolysis in adipocytes elicited by HFD feeding is linked with enhanced gluconeogenesis from glycerol and with alterations in BA physiology in Insr(P1195L/+)/HFD liver.
  • Tang L, Okamoto S, Shiuchi T, Toda C, Takagi K, Sato T, Saito K, Yokota S, Minokoshi Y
    Endocrinology 156 10 3680 - 3694 2015年10月 [査読有り][通常論文]
     
    Adipose tissue macrophages (ATMs) play an important role in the inflammatory response in obese animals. How ATMs are regulated in lean animals has remained elusive, however. We now show that the sympathetic nervous system (SNS) is necessary to maintain the abundance of the mRNA for the proinflammatory cytokine TNF-alpha at a low level in ATMs of lean mice. Intracerebroventricular injection of agouti-related neuropeptide increased the amount of TNF-alpha mRNA in epididymal (epi) white adipose tissue (WAT), but not in interscapular brown adipose tissue (BAT), through inhibition of sympathetic nerve activity in epiWAT. The surgical denervation and beta-adrenergic antagonist propranolol up-regulated TNF-alpha mRNA in both epiWAT and BAT in vivo. Signaling by the beta(2)-adrenergic receptor (AR) and protein kinase A down-regulated TNF-alpha mRNA in epiWAT explants and suppressed lipopolysaccharide-induced up-regulation of TNF-alpha mRNA in the stromal vascular fraction of this tissue. beta-AR-deficient (beta-less) mice manifested an increased plasma TNF-alpha concentration and increased TNF-alpha mRNA abundance in epiWAT and BAT. TNF-alpha mRNA abundance was greater in ATMs (CD11b(+) cells of the stromal vascular fraction) from epiWAT or BAT of wild-type mice than in corresponding CD11b(+) cells, and beta(2)-AR mRNA abundance was greater in ATMs than in CD11b(+) cells of epiWAT. Our results show that the SNS and beta(2)-AR-protein kinase A pathway maintain an anti-inflammatory state in ATMs of lean mice in vivo, and that the brain melanocortin pathway plays a role in maintaining this state in WAT of lean mice via the SNS.
  • Chitoku Toda, Sabrina Diano
    BEST PRACTICE & RESEARCH CLINICAL ENDOCRINOLOGY & METABOLISM 28 5 757 - 764 2014年10月 [査読有り][通常論文]
     
    Uncoupling protein 2 (UCP2) is a mitochondrial anion carrier protein, which uncouples the oxidative phosphorylation from ATP production by dissipating the proton gradient generated across the mitochondrial inner membrane. UCP2 regulates not only mitochondrial TP production, but also the generation of reactive oxygen species (ROS), considered important second-messenger signals within the cell. The importance of UCP2 was firstly reported in macrophages and pancreatic beta cells. However, several studies have revealed the important role of UCP2 in the Central Nervous System (CNS) in the regulation of homeostatic mechanisms including food intake, energy expenditure, glucose homeostasis and reward behaviors. The mechanisms by which central UCP2 affect these processes seem to be associated with synaptic and mitochondrial plasticity. In this review, we will describe recent findings on central UCP2 and discuss its role in CNS regulation of homeostasis. (C) 2014 Published by Elsevier Ltd.
  • Long L, Toda C, Jeong JK, Horvath TL, Diano S
    The Journal of clinical investigation 124 9 4017 - 4027 2014年09月 [査読有り][通常論文]
     
    Activation of central PPAR gamma promotes food intake and body weight gain; however, the identity of the neurons that express PPAR gamma and mediate the effect of this nuclear receptor on energy homeostasis is unknown. Here, we determined that selective ablation of PPAR gamma in murine proopiomelanocortin (POMC) neurons decreases peroxisome density, elevates reactive oxygen species, and induces leptin sensitivity in these neurons. Furthermore, ablation of PPAR gamma in POMC neurons preserved the interaction between mitochondria and the endoplasmic reticulum, which is dysregulated by HFD. Compared with control animals, mice lacking PPAR gamma in POMC neurons had increased energy expenditure and locomotor activity; reduced body weight, fat mass, and food intake; and improved glucose metabolism when exposed to high-fat diet (HFD). Finally, peripheral administration of either a PPAR gamma activator or inhibitor failed to affect food intake of mice with POMC-specific PPAR gamma ablation. Taken together, our data indicate that PPAR gamma mediates cellular, biological, and functional adaptations of POMC neurons to HFD, thereby regulating whole-body energy balance.
  • Jung Dae Kim, Chitoku Toda, Giuseppe D'Agostino, Caroline J. Zeiss, Ralph J. DiLeone, John D. Elsworth, Richard G. Kibbey, Owen Chan, Brandon K. Harvey, Christopher T. Richie, Mari Savolainen, Timo Myohanen, Jin Kwon Jeong, Sabrina Diano
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 111 32 11876 - 11881 2014年08月 [査読有り][通常論文]
     
    Prolyl endopeptidase (PREP) has been implicated in neuronal functions. Here we report that hypothalamic PREP is predominantly expressed in the ventromedial nucleus (VMH), where it regulates glucose-induced neuronal activation. PREP knockdown mice (Prep(gt/gt)) exhibited glucose intolerance, decreased fasting insulin, increased fasting glucagon levels, and reduced glucose-induced insulin secretion compared with wild-type controls. Consistent with this, central infusion of a specific PREP inhibitor, S17092, impaired glucose tolerance and decreased insulin levels in wild-type mice. Arguing further for a central mode of action of PREP, isolated pancreatic islets showed no difference in glucose-induced insulin release between Prep(gt/gt) and wild-type mice. Furthermore, hyperinsulinemic euglycemic clamp studies showed no difference between Prep(gt/gt) and wild-type control mice. Central PREP regulation of insulin and glucagon secretion appears to be mediated by the autonomic nervous system because Prep(gt/gt) mice have elevated sympathetic outflow and norepinephrine levels in the pancreas, and propranolol treatment reversed glucose intolerance in these mice. Finally, re-expression of PREP by bilateral VMH injection of adeno-associated virus-PREP reversed the glucose-intolerant phenotype of the Prep(gt/gt) mice. Taken together, our results unmask a previously unknown player in central regulation of glucose metabolism and pancreatic function.
  • Hiroshi Kitamura, Shunsuke Kimura, Yoshinori Shimamoto, Jun Okabe, Masatoshi Ito, Tomomi Miyamoto, Yoshinori Naoe, Chisato Kikuguchi, Bob Meek, Chitoku Toda, Shiki Okamoto, Katsushi Kanehira, Koji Hase, Hiroshi Watarai, Mayumi Ishizuka, Assam El-Osta, Osamu Ohara, Ichiro Miyoshi
    FASEB Journal 27 12 4940 - 4953 2013年12月 [査読有り][通常論文]
     
    Macrophages play a critical role in chronic inflammation and metabolic diseases. We identified a longer splice variant of ubiquitin specific protease (USP) 2-69 as a novel molecule that modulates pathways implicated in metabolic disorders. Expression levels of aP2/ FABP4 and PAI-1/SERPINE1 genes were increased by 4- and 1.8-fold, respectively, after short hairpin RNA-mediated knockdown (KD) of the USP2 gene, and such expression was alleviated by overexpression of USP2-69 in human myeloid cell lines. Supernatants derived from USP2-KD cells induced IL6 (6-fold) and SAA3 (15-fold) in 3T3-L1 adipocytes to suggest the anti-inflammatory properties of USP2. In addition, we observed a 30% decrease in the number of macrophages in mesenteric adipose tissue derived from USP2-69 transgenic mice fed a high-fat diet for 14 wk compared with that in their C57BL/6 littermates (P< 0.01), which was consistent with a 40% decrease in transcription of aP2 and PAI-1. The aP2 locus exhibited elevated chromatin accessibility (> 2.1-fold), methylation of histone H3 lysine 4 (> 4.5- fold), and acetylation of histone H4 (> 2.5-fold) in USP2-KD cells. Transfection of isopeptidase-mutated USP2-69 did not alter chromatin conformation on the aP2 locus in USP2-KD cells. Our results suggest that USP2-69 suppresses meta-inflammatory molecules involved in the development of type-2 diabetes.-Kitamura, H., Kimura, S., Shimamoto, Y., Okabe, J., Ito, M., Miyamoto, T., Naoe, Y., Kikuguchi, C., Meek, B., Toda, C., Okamoto, S., Kanehira, K., Hase, K., Watarai, H., Ishizuka, M., El-Osta, A., Ohara, O., Miyoshi, I. Ubiquitin-specific protease 2-69 in macrophages potentially modulates metainflammation. © FASEB.
  • Hiroshi Kitamura, Shunsuke Kimura, Yoshinori Shimamoto, Jun Okabe, Masatoshi Ito, Tomomi Miyamoto, Yoshinori Naoe, Chisato Kikuguchi, Bob Meek, Chitoku Toda, Shiki Okamoto, Katsushi Kanehira, Koji Hase, Hiroshi Watarai, Mayumi Ishizuka, Assam El-Osta, Osamu Ohara, Ichiro Miyoshi
    FASEB JOURNAL 27 12 4940 - 4953 2013年12月 [査読有り][通常論文]
     
    Macrophages play a critical role in chronic inflammation and metabolic diseases. We identified a longer splice variant of ubiquitin specific protease (USP) 2-69 as a novel molecule that modulates pathways implicated in metabolic disorders. Expression levels of aP2/FABP4 and PAI-1/SERPINE1 genes were increased by 4- and 1.8-fold, respectively, after short hairpin RNA-mediated knockdown (KD) of the USP2 gene, and such expression was alleviated by overexpression of USP2-69 in human myeloid cell lines. Supernatants derived from USP2-KD cells induced IL6 (similar to 6-fold) and SAA3 (similar to 15-fold) in 3T3-L1 adipocytes to suggest the anti-inflammatory properties of USP2. In addition, we observed a 30% decrease in the number of macrophages in mesenteric adipose tissue derived from USP2-69 transgenic mice fed a high-fat diet for 14 wk compared with that in their C57BL/6 littermates (P<0.01), which was consistent with a similar to 40% decrease in transcription of aP2 and PAI-1. The aP2 locus exhibited elevated chromatin accessibility (>2.1-fold), methylation of histone H3 lysine 4 (>4.5-fold), and acetylation of histone H4 (>2.5-fold) in USP2-KD cells. Transfection of isopeptidase-mutated USP2-69 did not alter chromatin conformation on the aP2 locus in USP2-KD cells. Our results suggest that USP2-69 suppresses meta-inflammatory molecules involved in the development of type-2 diabetes.
  • Kitamura H, Naoe Y, Kimura S, Miyamoto T, Okamoto S, Toda C, Shimamoto Y, Iwanaga T, Miyoshi I
    Adipocyte 2 4 227 - 236 2013年10月 [査読有り][通常論文]
  • Chitoku Toda, Tetsuya Shiuchi, Haruaki Kageyama, Shiki Okamoto, Eulalia A. Coutinho, Tatsuya Sato, Yuko Okamatsu-Ogura, Shigefumi Yokota, Kazuyo Takagi, Tang Tang, Kumiko Saito, Seiji Shioda, Yasuhiko Minokoshi
    Diabetes 62 7 2295 - 2307 2013年07月 [査読有り][通常論文]
     
    Leptin is a key regulator of glucose metabolism in mammals, but the mechanisms of its action have remained elusive. We now show that signaling by extracellular signal-regulated kinase (ERK) and its upstream kinase MEK in the ventromedial hypothalamus (VMH) mediates the leptin-induced increase in glucose utilization as well as its insulin sensitivity in the whole body and in red-type skeletal muscle of mice through activation of the melanocortin receptor (MCR) in the VMH. In contrast, activation of signal transducer and activator of transcription 3 (STAT3), but not the MEK-ERK pathway, in the VMH by leptin enhances the insulin-induced suppression of endogenous glucose production in an MCR-independent manner, with this effect of leptin occurring only in the presence of an increased plasma concentration of insulin. Given that leptin requires 6 h to increase muscle glucose uptake, the transient activation of the MEK-ERK pathway in the VMH by leptin may play a role in the induction of synaptic plasticity in the VMH, resulting in the enhancement of MCR signaling in the nucleus and leading to an increase in insulin sensitivity in red-type muscle. © 2013 by the American Diabetes Association.
  • Chitoku Toda, Tetsuya Shiuchi, Haruaki Kageyama, Shiki Okamoto, Eulalia A. Coutinho, Tatsuya Sato, Yuko Okamatsu-Ogura, Shigefumi Yokota, Kazuyo Takagi, Lijun Tang, Kumiko Saito, Seiji Shioda, Yasuhiko Minokoshi
    DIABETES 62 7 2295 - 2307 2013年07月 [査読有り][通常論文]
     
    Leptin is a key regulator of glucose metabolism in mammals, but the mechanisms of its action have remained elusive. We now show that signaling by extracellular signal-regulated kinase (ERK) and its upstream kinase MEK in the ventromedial hypothalamus (VMH) mediates the leptin-induced increase in glucose utilization as well as its insulin sensitivity in the whole body and in red-type skeletal muscle of mice through activation of the melanocordn receptor (MCR) in the VMH. In contrast, activation of signal transducer and activator of transcription 3 (STAT3), but not the MEK-ERK pathway, in the VMH by leptin enhances the insulin-induced suppression of endogenous glucose production in an MCR-independent manner, with this effect of leptin occurring only in the presence of an increased plasma concentration of insulin. Given that leptin requires 6 h to increase muscle glucose uptake, the transient activation of the MEK-ERK pathway in the VMH by leptin may play a role in the induction of synaptic plasticity in the VMH, resulting in the enhancement of MCR signaling in the nucleus and leading to an increase in insulin sensitivity in red-type muscle.
  • Minokoshi Y, Toda C, Okamoto S
    Indian journal of endocrinology and metabolism 16 Suppl 3 S562 - 8 2012年12月 [査読有り][通常論文]
  • Miyako Tanaka, Takayoshi Suganami, Misa Kim-Saijo, Chitoku Toda, Makoto Tsuiji, Kozue Ochi, Yasutomi Kamei, Yasuhiko Minokoshi, Yoshihiro Ogawa
    JOURNAL OF NEUROSCIENCE 31 23 8373 - 8380 2011年06月 [査読有り][通常論文]
     
    Nutritional deprivation or malnutrition suppresses immune function in humans and animals, thereby conferring higher susceptibility to infectious diseases. Indeed, nutritional deprivation induces atrophy of lymphoid tissues such as thymus and spleen and decreases the number of circulating lymphocytes. Leptin, a major adipocytokine, is exclusively produced in the adipose tissue in response to the nutritional status and acts on the hypothalamus, thereby regulating energy homeostasis. Although leptin plays a critical role in the starvation-induced T-cell-mediated immunosuppression, little is known about its role in B-cell homeostasis under starvation conditions. Here we show the alteration of B-cell development in the bone marrow of fasted mice, characterized by decrease in pro-B, pre-B, and immature B cells and increase in mature B cells. Interestingly, intracerebroventricular leptin injection was sufficient to prevent the alteration of B-cell development of fasted mice. The alteration of B lineage cells in the bone marrow of fasted mice was markedly prevented by oral administration of glucocorticoid receptor antagonist RU486 (11 beta-[p-(dimethylamino)phenyl]-17 beta-hydroxy-17-(1-propynyl) estra-4,9-dien-3-one). It was also effectively prevented by intracerebroventricular injection of neuropeptide Y Y(1) receptor antagonist BIBP3226 [(2R)-5-(diaminomethylideneamino)-2-[(2,2-diphenylacetyl) amino]-N-[(4-hydroxyphenyl) methyl] pentanamide], along with suppression of the otherwise increased serum corticosterone concentrations. This study provides the first in vivo evidence for the role of central leptin signaling in the starvation-induced alteration of B-cell development. The data of this study suggest that the CNS, which is inherent to integrate information from throughout the organism, is able to control immune function.
  • Kumiko Saito, Suni Lee, Tetsuya Shiuchi, Chitoku Toda, Masahiro Kamijo, Kyoko Inagaki-Ohara, Shiki Okamoto, Yasuhiko Minokoshi
    ANALYTICAL BIOCHEMISTRY 412 1 9 - 17 2011年05月 [査読有り][通常論文]
     
    An enzymatic assay adapted to photometric analysis with 96-well microplates was evaluated for the measurement of 2-deoxyglucose (2DG) uptake in insulin-responsive tissues and differentiated 313-L1 adipocytes. For in vivo measurements, a small amount of nonradiolabeled 2DG was injected into mice without affecting glucose metabolism. For photometric quantification of the small amount of 2-deoxyglucose 6-phosphate (2DG6P) that accumulates in cells, we introduced glucose-6-phosphate dehydrogenase, glutathione reductase, and 5,5'-dithiobis(2-nitrobenzoic acid) to the recycling amplification reaction of NADPH. We optimized the enzyme reaction for complete oxidation of endogenous glucose 6-phosphate (G6P) and glucose in mouse tissues in vivo and serum as well as in 313-L1 adipocytes in vitro. All reactions are performed in one 96-well microplate by consecutive addition of reagents, and the assay is able to quantify 2DG and 2DG6P in the range of 5-80 pmol. The results obtained with the assay for 2DG uptake in vitro and in vivo in the absence or presence of insulin stimulation was similar to those obtained with the standard radioisotopic method. Thus, the enzymatic assay should prove to be useful for measurement of 2DG uptake in insulin-responsive tissues in vivo as well as in cultured cells. (C) 2011 Elsevier Inc. All rights reserved.
  • Kumiko Saito, Suni Lee, Tetsuya Shiuchi, Chitoku Toda, Masahiro Kamijo, Kyoko Inagaki-Ohara, Shiki Okamoto, Yasuhiko Minokoshi
    Analytical Biochemistry: Methods in the Biological Sciences Vol.412 No.1 9 - 17 2011年01月22日 [査読有り][通常論文]
     
    An enzymatic assay adapted to photometric analysis with 96-well microplates was evaluated for the measurement of 2-deoxyglucose (2DG) uptake in insulin-responsive tissues and differentiated 3T3-L1 adipocytes. For in vivo measurements, a small amount of nonradiolabeled 2DG was injected into mice without affecting glucose metabolism. For photometric quantification of the small amount of 2-deoxyglucose 6-phosphate (2DG6P) that accumulates in cells, we introduced glucose-6-phosphate dehydrogenase, glutathione reductase, and 5,5'-dithiobis(2-nitrobenzoic acid) to the recycling amplification reaction of NADPH. We optimized the enzyme reaction for complete oxidation of endogenous glucose 6-phosphate (G6P) and glucose in mouse tissues in vivo and serum as well as in 3T3-L1 adipocytes in vitro. All reactions are performed in one 96-well microplate by consecutive addition of reagents, and the assay is able to quantify 2DG and 2DG6P in the range of 5-80 pmol. The results obtained with the assay for 2DG uptake in vitro and in vivo in the absence or presence of insulin stimulation was similar to those obtained with the standard radioisotopic method. Thus, the enzymatic assay should prove to be useful for measurement of 2DG uptake in insulin-responsive tissues in vivo as well as in cultured cells.
  • Toda C
    Nihon rinsho. Japanese journal of clinical medicine 69 Suppl 1 133 - 137 2011年01月 [査読有り][通常論文]
  • Chitoku Toda, Tetsuya Shiuchi, Suni Lee, Maya Yamato-Esaki, Yusuke Fujino, Atsushi Suzuki, Shiki Okamoto, Yasuhiko Minokoshi
    Diabetes 58 12 2757 - 2765 2009年12月 [査読有り][通常論文]
     
    OBJECTIVE - The medial hypothalamus mediates leptin-induced glucose uptake in peripheral tissues, and brain melanocortin receptors (MCRs) mediate certain central effects of leptin. However, the contributions of the leptin receptor and MCRs in individual medial hypothalamic nuclei to regulation of peripheral glucose uptake have remained unclear. We examined the effects of an injection of leptin and the MCR agonist MT-II into medial hypothalamic nuclei on glucose uptake in peripheral tissues. RESEARCH DESIGN AND METHODS - Leptin or MT-II was injected into the ventromedial (VMH), dorsomedial (DMH), arcuate nucleus (ARC), or paraventricular (PVH) hypothalamus or the lateral ventricle (intracerebroventricularly) in freely moving mice. The MCR antagonist SHU9119 was injected intracerebroventricularly. Glucose uptake was measured by the 2-[3H]deoxy-D-glucose method. RESULTS - Leptin injection into the VMH increased glucose uptake in skeletal muscle, brown adipose tissue (BAT), and heart, whereas that into the ARC increased glucose uptake in BAT, and that into the DMH or PVH had no effect. SHU9119 abolished these effects of leptin injected into the VMH. Injection of MT-II either into the VMH or intracerebroventricularly increased glucose uptake in skeletal muscle, BAT, and heart, whereas that into the PVH increased glucose uptake in BAT, and that into the DMH or ARC had no effect. CONCLUSIONS - The VMH mediates leptin- and MT-II - induced glucose uptake in skeletal muscle, BAT, and heart. These effects of leptin are dependent on MCR activation. The leptin receptor in the ARC and MCR in the PVH regulate glucose uptake in BAT. Medial hypothalamic nuclei thus play distinct roles in leptin- and MT-II - induced glucose uptake in peripheral tissues. © 2009 by the American Diabetes Association.
  • Chitoku Toda, Tetsuya Shiuchi, Suni Lee, Maya Yamato-Esaki, Yusuke Fujino, Atsushi Suzuki, Shiki Okamoto, Yasuhiko Minokoshi
    DIABETES 58 12 2757 - 2765 2009年12月 [査読有り][通常論文]
     
    OBJECTIVE-The medial hypothalamus mediates leptin-induced glucose uptake in peripheral tissues, mid brain melanocortin receptors (MCRs) mediate certain central effects of leptin. However, the contributions of the leptin receptor and MCRs in individual medial hypothalamic nuclei to regulation of peripheral glucose uptake have remained unclear. We examined the effects of an injection of leptin and the MCR agonist MT-II into medial hypothalamic nuclei on glucose uptake in peripheral tissues. RESEARCH DESIGN AND METHODS-Leptin or MT-II was injected into the ventromedial (VMH), dorsomedial (DMH), arcuate nucleus (ARC), or paraventricular (PVH) hypothalamus or the lateral ventricle (intracerebroventricularly) in freely moving mice. The MCR antagonist SHU9119 was injected intracerebroventricularly. Glucose uptake was measured by the 2-[(3)H]deoxy-D-glucose method. RESULTS-Leptin injection into the VMH increased glucose uptake in skeletal muscle, brown adipose tissue (BAT), and heart, whereas that into the ARC increased glucose uptake in BAT, and that, into the DMH or PVH had no effect. SHU9119 abolished these effects of leptin injected into the VMH. Injection of MT-II either into the VMH or intracerebroventricularly increased glucose uptake in skeletal muscle, BAT, and heart, whereas that into the PVH increased glucose uptake in BAT, and that into the DMH or ARC had no effect. CONCLUSIONS-The VMH mediates leptin- and MT-II-induced glucose uptake in skeletal muscle, BAT, and heart. These effects of leptin are dependent on MCR activation. The leptin receptor in the ARC and MCR in the PVH regulate glucose uptake in BAT. Medial hypothalamic nuclei thus play distinct roles in leptin- and MT-II-induced glucose uptake in peripheral tissues. Diabetes 58:2757-2765, 2009
  • Tetsuya Shiuchi, Mohammad Shahidul Haque, Shiki Okamoto, Tsuyoshi Inoue, Haruaki Kageyama, Suni Lee, Chitoku Toda, Atsushi Suzuki, Eric S. Bachman, Young-Bum Kim, Takashi Sakurai, Masashi Yanagisawa, Seiji Shioda, Keiji Imoto, Yasuhiko Minokoshi
    CELL METABOLISM 10 6 466 - 480 2009年12月 [査読有り][通常論文]
     
    Hypothalamic neurons containing orexin (hypocretin) are activated during motivated behaviors and active waking. We show that injection of orexin-A into the ventromedial hypothalamus (VMH) of mice or rats increased glucose uptake and promoted insulin-induced glucose uptake and glycogen synthesis in skeletal muscle, but not in white adipose tissue, by activating the sympathetic nervous system. These effects of orexin were blunted in mice lacking beta-adrenergic receptors but were restored by forced expression of the beta(2)-adrenergic receptor in both myocytes and nonmyocyte cells of skeletal muscle. Orexin neurons are activated by conditioned sweet tasting and directly excite VMH neurons, thereby increasing muscle glucose metabolism and its insulin sensitivity. Orexin and its receptor in VMH thus play a key role in the regulation of muscle glucose metabolism associated with highly motivated behavior by activating muscle sympathetic nerves and beta(2)-adrenergic signaling.
  • Yuko Okamatsu-Ogura, Akihiro Uozumi, Chitoku Toda, Kazuhiro Kimura, Hitoshi Yamashita, Masayuki Saito
    OBESITY RESEARCH & CLINICAL PRACTICE 1 4 233 - 241 2007年12月 [査読有り][通常論文]
     
    Leptin is proposed to reduce body fat by increasing energy expenditure, in addition to decreasing food intake, through the activation of brown adipose tissue (BAT) thermogenesis. To confirm this, we investigated the effects of leptin on whole body energy expenditure, BAT functions and adiposity in wild-type (WT) mice, and compared with those in mice deficient in uncoupling protein 1 (UCP1), a key molecule for BAT thermogenesis. Chronic hyperleptinemia induced by adenovirus gene transfer reduced food intake in both WT and UCP1-KO mice. WT mice with hyperleptinemia, compared to pair-fed controls, showed increased oxygen consumption, elevated UCP1 expression in BAT, ectopic UCP1 induction in white adipose tissue (WAT), and reduced body fat content. These effects of chronic hyperleptinemia were not observed in UCP1-KO mice. It was concluded that the fat-reducing effect of leptin is due to not only decreased food intake, but also increased UCP1-dependent energy expenditure. (c) 2007 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.
  • Omachi, A, Ishioka, K, Uozumi, A, Kamikawa, A, Toda, C, Kimura, K, Saito, M
    Research in Veterinary Science 83 1 5 - 11 2007年08月 [査読有り][通常論文]
     
    A selective β3-adrenoceptor agonist, AJ-9677, was reported to ameliorate obesity and insulin resistance in KK-Ay mice. We examined the acute and chronic effects of AJ-9677 on obese dogs. Oral administration of AJ-9677 (0.01 or 0.1 mg/kg) to overnight fasted obese beagles produced a dose-dependent rise in the plasma levels of non-esterified fatty acids and insulin in 1 h, followed by a gradual drop of the plasma glucose level. It produced no apparent abnormal behaviors, but easily detectable cutaneous flushing. Daily treatment of AJ-9677 at a lower dose (0.01 mg/kg) for three weeks produced no notable change in body weight, but at a higher dose (0.1 mg/kg) it reduced the body weight compared to a placebo treatment after seven weeks. Computed tomographic examinations revealed a remarkable reduction of body fat after the AJ treatment, being consistent with the histological observations that the adipose tissue of AJ-9677-treated dogs consisted of smaller and some multilocular adipocytes. The plasma levels of leptin and adiponectin were decreased and increased, respectively, after the AJ treatment, reflecting the reduction of adiposity. It was concluded that AJ-9677 is useful for the treatment of obesity in the dog. © 2006 Elsevier Ltd. All rights reserved.
  • K Inokuma, Y Ogura-Kamatsu, C Toda, K Kimura, H Yamashita, M Saito
    DIABETES 54 5 1385 - 1391 2005年05月 [査読有り][通常論文]
     
    Sympathetic stimulation activates glucose utilization in parallel with fatty acid oxidation and thermogenesis in brown adipose tissue (BAT) through the beta-adrenergic receptors. To clarify the roles of the principal thermogenic molecule mitochondrial uncoupling protein 1 (UCP1) in the sympathetically stimulated glucose utilization, we investigated the uptake of 2-deoxyglucose (2-DG) into BAT and some other tissues of UCP1-knockout (KO) mice in vivo. In wild-type (WT) mice, administration of norepinephrine (NE) accelerated the disappearance of plasma 2-DG and increased 2-DG uptake into BAT and heart without any rise of plasma insulin level. In UCP1-KO mice, the stimulatory effect of NE on 2-DG uptake into BAT, but not into heart, disappeared completely. Insulin administration increased 2-DG uptake into BAT and also heart similarly in WT and UCP1-KO mice. NE also increased the activity of AMP-activated protein kinase (AMP kinase) in BAT of WT but not UCP1-KO mice. Our results, together with reports that the activation of AMP kinase increases glucose transport in myocytes, suggest that the sympathetically stimulated glucose utilization in BAT is due to the serial activation of UCP1 and AMP kinase.
  • 2016 AMPK-fatty acid oxidation in PVH neurons controls food selection behavior.
    Okamoto S, Shiuchi T, Maejima Y, Kageyama H, Matsuo T, Kamijo M, Kyaw S, Lee S, Toda C, Saito K, Suzuki A, Foufelle F, Ferre P, Shioda S, Yada T, Minokoshi Y
    Cell [査読有り][通常論文]

その他活動・業績

受賞

  • 2016年 日本肥満学会 若手研究奨励賞

共同研究・競争的資金等の研究課題

  • 視床下部における神経回路の変化と全身糖代謝調節の関係解明
    日本学術振興会:科学研究費助成事業 基盤研究(B)
    研究期間 : 2021年04月 -2025年03月 
    代表者 : 戸田 知得
  • 神経向性ウィルス複製における粘膜組織微生物群の役割
    日本学術振興会:科学研究費助成事業 基盤研究(B)
    研究期間 : 2018年04月 -2022年03月 
    代表者 : 飯島 則文, 戸田 知得
     
    粘膜組織には、病原微生物が侵入する以前に、既に様々な微生物叢が常在しており、互いに共存する形で粘膜組織の機能維持に重要な役割を果たしている。ウイルスのような病原微生物が侵入する際には、このような常在微生物叢が構成する微小環境を通り抜けて、粘膜組織から神経組織へと侵入することになる。 そこで、神経向性ウイルス感染に対する粘膜組織微生物群の役割を明らかにするためには、まず神経向性ウィルスが感染後にどのような免疫担当細胞が集積するのか、集積した免疫担当細胞がどのようにしてウイルス複製を抑制するのか明らかにする必要がある。 まず、神経向性ウイルス感染後の粘膜組織における生体防御機構に着目し、ウイルスを排除するメカニズムを明らかにすることを目的とした。これまでに粘膜組織へのメモリーB 細胞の移行を解析したところ、神経向性ウイルスに一度感染したマウスでは、ウイルス再感染後にメモリーB 細胞の数が著しく増大することを報告してきた。今回、生殖粘膜組織へのメモリー B 細胞の移行にケモカイン受容体 CXCR3 が重要な役割を果たし、ウイルス再感染後のウイルス複製抑制機構に重要な役割を果たしていることを明らかにした。また、CXCR3 に反応するリガンドは、粘膜組織に長期間局在する組織局在型メモリー T 細胞から分泌される IFN-g を介して分泌されることが明らかとなり、ウイルス再感染による抗原特異的反応に依存して、メモリー B 細胞が粘膜組織へと移行できることも発見した。今後は、生殖粘膜組織へのメモリー B 細胞の機能に着目して、組織への維持機構や侵入する病原体を排除する詳細なメカニズムを解析する予定である。
  • 視床下部グルコース感受性神経における新たな調節因子と抗糖尿病薬の探索
    日本学術振興会:科学研究費助成事業 若手研究(A)
    研究期間 : 2017年04月 -2021年03月 
    代表者 : 戸田 知得
     
    本研究の目的は、生活習慣病においてどのような分子が脳による血糖値の変化感知機能を低下し、糖尿病発症に関与するかを明らかにすると共に、その分子が糖尿病治療のターゲット分子となり得るかを明らかにすることである。2019年度は以下の研究成果を得た。
    ①通常マウスと肥満マウスにおいて、グルコースによって活性化される神経細胞(グルコース興奮性神経)のsingle cell RNA sequence行った結果、糖尿病を改善する効果がある分子Aを発見した(特許出願中)。②分子Aの作用メカニズムを解明するために様々な阻害剤を用いたところ、分子AはWntシグナルを介して抗糖尿病作用を示すことを明らかにした。③Wntシグナルは海馬の神経細胞においてシナプスの形態変化に関与することが知られている。従って、分子Aを投与したときのグルコース興奮性神経のシナプス数を測定したところ、分子Aがシナプスの数を増加させることを見出した。④分子Aによる抗糖尿病作用の分子メカニズムを解明するために、肥満マウスに分子Aを投与した後にグルコース興奮性神経を取り出しsingle cell RNA sequence行った。現在、遺伝子発現の変化を解析中である。⑤肥満による糖代謝悪化の分子Aとは異なるメカニズムを発見するために、視床下部のイメージング質量分析を行った。その結果、肥満モデルマウスの視床下部では通常マウスよりもアラキドン酸を含有する細胞膜リン脂質が低下し、プロスタグランジン類の生成が増加した。リン脂質からアラキドン酸を遊離するホスホリパーゼA2の発現をshRNAによって低下させると糖代謝が改善した。
  • 日本学術振興会:科学研究費助成事業 基盤研究(B)
    研究期間 : 2012年04月 -2015年03月 
    代表者 : 箕越 靖彦, 岡本 士毅, 戸田 知得
     
    レプチンが視床下部腹内側核( VMH)ニューロンを通してどのようにマウスにおいて代謝調節作用を営むかを、Hyperinsulinemic-euglycemic clampと2DG法を用いて調べた。また、代表的なVMHニューロンの一つであるAd4BPニューロンをDREADD法によって選択的に活性化し、摂食量と代謝に及ぼす効果を調べた。レプチンは、骨格筋と肝臓のインスリン感受性を高め、骨格筋での糖取込を促進する一方、肝臓からの糖産生を抑制した。Ad4BPニューロンをDREADD法によって選択的に活性化することによっても、骨格筋と肝臓でのインスリン感受性を高めた。また摂食も抑制した。
  • 日本学術振興会:科学研究費助成事業 若手研究(B)
    研究期間 : 2011年 -2012年 
    代表者 : 戸田 知得
     
    我々は、レプチンが視床下部腹内側核のニューロンに作用して骨格筋および肝臓のインスリン感受性を亢進することを明らかにした。さらにそのメカニズムとして腹内側核ニューロンにおけるMEK/ERK 経路およびJak/STAT3 経路がそれぞれ骨格筋および肝臓 のインスリン感受性を亢進することを見いだした。特に骨格筋におけるレプチンの糖代謝亢進作用には視床下部弓状核に存在するPOMC ニューロンが活性化され、その神経終末から放出されるalpha-MSH が腹内側核に作用することが重要であることも明らかにした。

教育活動情報

主要な担当授業

  • 獣医科学基礎科目B 生命科学特論Ⅰ:実験の原理
    開講年度 : 2020年
    課程区分 : 博士後期課程
    開講学部 : 獣医学研究科
  • 先端生命科学特論Ⅲ
    開講年度 : 2020年
    課程区分 : 博士後期課程
    開講学部 : 獣医学院
  • 生化学実習
    開講年度 : 2020年
    課程区分 : 学士課程
    開講学部 : 獣医学部
  • 生化学実習
    開講年度 : 2020年
    課程区分 : 学士課程
    開講学部 : 獣医学部
    キーワード : 溶液とpH、蛋白質の定量、糖質の定量、脂質の定量、核酸の定量、酵素反応速度


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