代謝、摂食調節 Metabolism and Regulation of Food Intake
P1-2-143 ヒヨコの視床下部腹内側核におけるグルコースによる摂食調節機構 Mechanism of feeding regulation by glucose in the ventromedial hypothalamic nucleus in chick ○中森智啓1,2,3, 長嶋亮4, 浜崎浩子3, 佐藤勝重1,2 ○Tomoharu Nakamori1,2,3, Ryo Nagashima4, Hiroko Ohki-Hamazaki3, Katsushige Sato1,2 ヒューマンフロンティアサイエンス1, 駒沢女子大学　健康栄養学2, 北里大学　一般教育部生物学3, 北里大学　理学部細部生物学4 Human Frontier Science Program1, Department of Health and Nutrition Sciences, Faculty of Human Health, Komazawa Woman University, Tokyo, Japan2, Division of Biology, College of Liberal Arts and Sciences, Kitasato University, Kanagawa, Japan3, Division of Cell Biology, Department of Biosciences, Kitasato University, Kanagawa, Japan4 Blood glucose level affects food intake in animals. Elevation of blood glucose level induces satiety and its reduction causes fasting. Fluctuation of glucose level is always monitored in several organs, including brain. The nucleus ventromedialis hypothalami (VMH) is known to be important for suppression of feeding. VMH cells are activated by elevation of glucose level. Lesion of the VMH induces overfeeding and results in obesity. However, it is still unclear how VMH cells perceive interstitial glucose level and regulate feeding. Using optical imaging analysis with acute brain slices, we found that when an electrical stimulation is applied to the arcuate nucleus, response amplitude of VMH cells increased in response to increases in glucose concentration. This response was inhibited by application of an antagonist for glucose transporter type 1 (GLUT1). In vivo, microinjection of glucose in VMH decreased food intake as predicted, and that of GLUT1 antagonist increased food intake. Since histological observation indicated that most of astrocytes in VMH expressed GLUT1, it is suggested that in VMH, glucose is first received by astrocytes expressing GLUT1. Role of lactate in food intake was also explored. These data suggest that lactate is served as a signal mediating the elevation of interstitial glucose level that reflects elevated energy status of the body.	P1-2-144 海馬領域分散神経回路網におけるブドウ糖濃度に依存した神経電気活動 Spontaneous electrical activity of hippocampal neurons depends on extracellular glucose concentration ○箕嶋渉1, 伊東嗣功1, 工藤卓1 ○Wataru Minoshima1, Hidekatsu Itoh1, Suguru N. Kudoh1 関西学院大学大学院　理工学研究科　情報科学専攻1 Graduated School of Kwansei Gakuin University, Sanda, Hyogo1 Cultured rat hippocampal neurons on a multi electrode array (MEA) dish are an useful material for network dynamics and its developmental change. Neurons autonomously form a complex network on a MEA dish and spontaneous electrical activity is often observed without any inputs from the external world. The spontaneous activity is generated by synaptic interactions between neurons and reflects an internal biochemical state of a whole neuronal network. The origin of electrical activity is electrochemical potential generated by active transport of ions, which requires catabolism of ATP. We elucidated relationship between spontaneous electrical activity and external glucose concentration. The spontaneous activity changed transiently, depending on the concentrations of external glucose, and we analyzed the number of electrical spikes of spontaneous activity. The number of electrical spikes in spontaneous activity increases depending on the concentration of external glucose. Interestingly, the number of spontaneous spikes is not only suppressed but turn to decrease. In the case of glucose concentration is 17.5 mM, the number of activity is the most, and then it decreases in the case of glucose concentration is more than 17.5 mM. In addition, the decrease of neuronal activity at high glucose concentration is concerned with excess glucose transportation. In addition, optimal glucose concentration depends on the concentration of glucose during culturing days. These results suggest that optimal glucose concentration for frequent activity in cultured neuronal network was changed by extracellular glucose concentration during development of cultured neurons.
P1-2-145 マウス視床下部における摂食関連遺伝子発現に対する幼児期母子分離による影響 Maternal Separation controls food intake gene expression in mouse hypothalamus ○平林京1, 吉田彩1, 益子宏美1, 下郡智美1 ○Miyako Hirabayashi1, Aya Yoshida1, Hiromi Mashiko1, Tomomi Shimogori1 理化学研究所脳科学総合研究センター視床発生研究チーム1 Molecular Mechanisms of Thalamus Development, BSI, RIKEN1 Eating disorders refer to a group of conditions defined by abnormal eating habits that may involve excessive food intake which contributes to weight gain and obesity. The precise cause of eating disorders is not entirely understood, but there is candidate molecule to control food intake and also there is evidence that it may be linked to other medical conditions and situations. For instance, experience of childhood abuse is prevalent among patients with eating disorders. However, how experience influence food intake gene expression, change neuronal activity and modify neuronal circuit is not well known. To understand this, we used neonatal maternal separation (MS) in mice as an animal model of stressful experience early in life, and try to reveal molecular mechanism, which develop abnormal neural circuit for excess food intake. The MS was performed daily for 3 hr during the first 20 days of birth and control pups were left undisturbed. After weaning, analysis of food intake and body weight of male pups showed significant increase. In these animals, we found decreased blood concentration of Trh (thyrotropin-releasing hormone), and also decreased number of cells, which express Trh mRNA in hypothalamus. We are currently searching for other molecules, which are expressed in the same neurons with Trh in hypothalamus. These works are groundwork to reveal molecular mechanism of experience dependent neural circuit development and control of animals' behavior.	P1-2-146 マウス舌の味蕾は膝神経節および錐体神経節に存在するメラノコルチン4受容体発現ニューロンの神経終末を受ける Tongue taste buds receive nerve terminals originating from melanocortin-4 receptor expressing neurons in the mouse geniculate and petrosal ganglia ○津森登志子1, 岡達郎1, 横田茂文1, 安井幸彦1 ○Toshiko Tsumori1, Tatsuro Oka1, Shigefumi Yokota1, Yukihiko Yasui1 島根大学医学部解剖学講座神経形態学1 Dept Anat & Morphol Neurosci, Shimane Univ Sch Med, Izumo1 The melanocortin system including melanocortin-4 receptor (MC4R) plays an important role in the control of feeding and energy expenditure. Using a transgenic mouse model in which green fluorescent protein (GFP) is produced under the control of the MC4R promoter (MC4R/GFP mouse), we have reported that the nodose ganglia contain many MC4R-expressing neurons, some of which send their fibers to the pancreatic islet cells. In the present study, we examine whether or not the geniculate and petrosal ganglion cells send their fibers to the tongue taste buds in the MC4R/GFP mouse. Under a confocal laser scanning microscope, we clearly observed that GFP-positive nerve fibers were distributed densely in the fungiform and circumvallate taste buds. Using double immunofluorescence staining for GFP and specific markers for taste cells, we showed that GFP-positive intragemmal fibers were closely apposed not only to phospholipase β2-positive (type II) taste cells but also to synaptosomal associating protein-positive (type III) taste cells. Some of the GFP-positive intragemmal fibers were also positive for calcitonin gene-related peptide, but none of them were positive for substance P. Using retrograde tracing with chorela toxin B subunit (CTb) in combination with immunohistochemistry for GFP, we further showed that the geniculate and petrosal ganglia contained a significant number of GFP-positive neurons labeled with CTb injected into the tongue. Taken together, these results suggest that the MC4R-expressing geniculate and petrosal ganglion cells may be implicated in the control of taste sensitivity.
P1-2-147 インスリンはインスリンシグナルと電位依存性カルシウム流入を介して求心性迷走神経に直截作用する Insulin directly activates vagal afferent neurons through insulin signaling pathway and voltage-dependent Ca2+ influx ○岩崎有作1, 下村健寿1中林肇2, 窪田直人3, 門脇孝3, 加計正文4, 矢田俊彦1,5 ○Yusaku Iwasaki1, Kenju Shimomura1, Enkh-Amar Ayush1, Hajime Nakabayashi2, Naoto Kubota3, Takashi Kadowaki3, Masafumi Kakei4, Toshihiko Yada1,5 自治医大・医・統合生理1, 金沢大・保健管理センター2, 東京大院・糖尿病代謝内科3, 自治医大・さいたま医療センター・総医第一4, 生理研・発達生理5 Dept Physiol, Jichi Med Univ, Shimotsuke, Japan1, Health Science Service Center, Kanazawa Univ, Kanazawa, Japan2, Dept Diabetes and Metabolic Diseases, Graduate School of Medicine, Univ of Tokyo, Tokyo, Japan3, First Dept of Med, Saitama Medical Center, Jichi Medical Univ, Saitama, Japan4, Dept Developmental Physiol, National Institute for Physiological Sciences, Okazaki, Japan5 Some of physiological functions of insulin, including glucose/lipid metabolism, satiety and neuroprotection, involve the alteration of brain activities. Insulin could signal to the brain via penetrating through the blood brain barrier and acting on the vagal afferents, while the latter remains unproved. This study sought to clarify whether insulin directly acts on the nodose ganglion neurons (NGNs) of the vagal afferents in mice. A fraction of NGNs were immunoreactive to insulin receptor. Insulin depolarized and increased cytosolic Ca2+ concentration ([Ca2+]i) in single NGNs, as shown by patch-clamp and fura-2 microfluorometric measurements. The insulin-induced [Ca2+]i increases were attenuated by voltage-dependent L- and N-type Ca2+ channel blockers, by phosphatidylinositol 3 kinase (PI3K) inhibitor, and in NGNs isolated from mice deficient of insulin receptor substrate-2 (IRS2). However, inhibitor of mitogen-activated protein kinase (MAPK) did not affect the insulin-induced [Ca2+]i increases. All of insulin responsive NGNs were activated by capsaicin, suggesting that the vagal afferents of C fibers respond to insulin. These data demonstrate that insulin directly activates vagal afferent neurons including those via insulin receptor-IRS2-PI3K-cascade, depolarization-gated Ca2+ influx and [Ca2+]i increases. These interactions could serve to convert the changes in systemic and pancreatic insulin to the neural signaling to the brain.	P1-2-148 ショ糖過剰摂取行動を示すマウスでは、ショ糖溶液の胃内投与による内臓感覚刺激への脳幹神経核の反応性が減弱する Reduced hindbrain response to visceral stimulation by intragastric infusion of a caloric sweetener in mice showing binge-like sugar overconsumption ○八十島安伸1, 山口恵里菜1, 志村剛1 ○Yasunobu Yasoshima1, Erina Yamaguchi1, Tsuyoshi Shimura1 大阪大院・人間科学・行動生理1 Div Behav Physiol, Dept Behav Sci, Grad Sch Human Sci, Osaka Univ, Suita1 Overconsumption is suggested to be associated with decreased feedback inhibitory signaling elicited by nutrient-induced visceral stimulation in animal models. However, a recent study has reported that binge-like excessive feeding experience increases meal-eliciting neuronal activation in the nucleus of tractus solitarius (NTS). To address the discrepancy in the visceral role in overconsumption models, we examined whether binge-like excessive sugar-taking experience might lead to decreased hindbrain responses to visceral signals elicited by a gastric nutritional load. Food-restricted C57/BL6J male mice received 10-day training with intermittent limited access to a palatable sucrose (0.5 M) and normal chow for only 4 h a day. Control animals received the same scheduled sucrose access without food deprivation. Training animals consumed a significantly increased (3-fold) amount of sucrose on day 10, but no increase in control animals. On the next day, fasted both groups of mice received an intragastric infusion of the sucrose solution. The NTS response in the both groups was evaluated using c-fos immunoreactivity as a neuronal activation marker. In control animals, many Fos-positive cells were found in the caudal and intermediate NTS regions. The number of Fos-positive cells in the intermediate NTS in trained mice was significantly less than that in control animals. No different activation of the rostral NTS between the groups was found. These results suggest that binge-like overconsumption associates with reduced hindbrain responses to nutrient-induced visceral stimulation.
P1-2-149 肥満メスマウスの産仔は統合失調症様行動を示す Maternal obesity leads to schizophrenia-like behaviors in the adult offspring in mice ○伊藤亨子1,2, 田中光一1,2 ○Yukiko Itou1,2, Kohichi Tanaka1,2 東京医歯大・難研・分子神経1, 東京医歯大・脳統合機能研セ2 Dept Molecular Neuroscience, Med Res Inst, Tokyo Med & Dent Univ1, Cent Brain Integ Res, Tokyo Med & Dent Univ2 Introduction: Maternal obesity has a significant impact on the health of offsprings through a lifetime. Recent etiological studies have indicated an involvement of maternal obesity in mental illness including depression, anxiety disorder, ADHD, and schizophrenia. However, there were little experimental evidences about the effects of maternal obesity on behaviors in the offspring. We, therefore, used high fat diet (HFD)-induced obese dams to investigate behavioral outcomes in their offsprings in mice. Method: Offsprings in experimental group (HFD-F1) were born from and nursed by female mice fed with HFD for 6 weeks. As a control, offsprings of normal diet-fed female mice (ND-F1) were used. Behavioral phenotype of offsprings was analyzed in adulthood, and transcript levels of genes related to schizophrenia were measured in prefrontal cortex by quantitative PCR after behavioral testing. Results: HFD-F1 mice exhibited impairment of prepulse inhibition. They also showed an increase in locomotor activity in novel environment, but not in familiar environment. Neither obvious features of depression-like behavior nor social withdrawal were seen in HFD-F1 mice. Anxiety-like behaviors were decreased in HFD-F1 mice. Taken together, the adult HFD-F1 mice displayed schizophrenia-like behaviors. Quantitative PCR indicated that, in prefrontal cortex, there was no difference in transcript levels of the genes examined between HFD-F1 mice and ND-F1 mice. However, there was a correlation between locomotor activity and transcript levels of DRD1 and Gabrd in the adult HFD-F1 mice. Conclusion: Diet-induced maternal obesity lead to schizophrenia-like behaviors in the adult offspring, providing experimental evidence that maternal obesity can disturb mental health in next generation.	P1-2-150 視床下部神経細胞における転写因子AFF4のAMPK/ACCシグナル伝達経路に対する新規活性化メカニズムの検討 A novel activation mechanism of AMP-activated protein kinase/acetyl-CoA carboxylase (AMPK/ACC) pathway by AFF4 in the hypothalamic neurons ○小森忠祐1, 野阪哲哉2, 北村俊雄3, 仙波恵美子1, 森川吉博1 ○Tadasuke Komori1, Tetsuya Nosaka2, Toshio Kitamura3, Emiko Senba1, Yoshihiro Morikawa1 和歌山県立医科大学　医学部　第二解剖1, 三重大学大学院医学系研究科　感染症制御医学分野2, 東京大学医科学研究所　先端医療研究センター　細胞療法分野3 Dept Anat & Neurobiol, Wakayama Med Univ, Wakayama1, Dept Microbiol, Mie Univ Graduate School Med, Mie2, Division of Cellular Therapy, Advanced Clinical Research Center, The Institute of Med Sci, Univ of Tokyo, Tokyo3 A fasting-induced hormone, ghrelin, regulates food intake and energy metabolism mainly through the activation of AMP-activated protein kinase/acetyl-CoA carboxylase (AMPK/ACC) pathway in the hypothalamus. In the previous meeting, we have shown that ghrelin induced a member of the AF4 family of transcription factors, AFF4, in the hypothalamus. In a hypothalamic neuronal cell line, GT1-7 cells, ghrelin markedly induced the expression of AFF4, suggesting that ghrelin directly induces the expression of AFF4 in the hypothalamus during fasting. In addition, the overexpression of AFF4 significantly increased the expression of AMPKα2 and phosphorylation of ACCα in GT1-7 cells. In the present study, we investigated the details of a novel activation mechanism of AMPK/ACC pathway by AFF4. The overexpression of AFF4 in GT1-7 cells specifically induced the expression of the AMPKα2 subunit, but failed to induce other AMPK subunits (α1, β1, β2, γ1, γ2, γ3). The expressions of AMPK upstream kinases, CaMKK2 and LKB1, were not changed by AFF4. The promoter activity of AMPKα2 gene was increased by AFF4, suggesting that AFF4 augments the transcription of AMPKα2 gene. In addition, phosphorylation of ACCα induced by AFF4 was not affected by compound C, an inhibitor of AMPK phosphorylation, suggesting that AFF4 phosphorylates ACCα independent of AMPK phosphorylation. To investigate the roles of AFF4 in AMPK/ACC pathway activated by ghrelin, we blocked AFF4 expression by using siRNA against AFF4. Silencing AFF4 significantly attenuated ghrelin-induced expression of AMPKα2 and phosphorylation of ACCα in GT1-7 cells. Thus, AFF4 may contribute to the activation of AMPK/ACC pathway by the novel mechanism, which is independent of AMPK phosphorylation.
P1-2-151 Withdrawn

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