摂食調節、ストレス応答 Food intake regulation, stress response
O1-9-4-1 アミノ酸依存性グルカゴン様ペプチド-1ホルモン分泌メカニズムの解析 Live cell imaging analysis of amino acids-induced glucagon-like peptide-1 secretion from endocrine cells ○大屋愛実1, 北口哲也2, 坪井貴司1 ○Manami Oya1, Tetsuya Kitaguchi2, Takashi Tsuboi1 東京大院・総合文化・生命環境1, 早稲田シンガポール研・早大2 Dep. of Life Sci, Grad Sch. of Arts and Sci, Univ. of Tokyo, Tokyo1, WABIOS, Waseda Univ, Singapore2 Glucagon like peptide-1 (GLP-1) is a peptide hormone secreted from enteroendocrine L cells. Some studies have found that GLP-1 acts as a neurotransmitter, which is recognized by GLP-1 receptors in the arcuate nucleus and decreases appetite. However, the precise molecular mechanisms of GLP-1 secretion from enteroendocrine L cells have not been elucidated yet. In the present study, we used GLUTag cells as an enteroendocrine L cell model to elucidate the molecular mechanisms of GLP-1 secretion. First, we performed RT-PCR analysis and found the expression of putative amino acids-sensing receptors, including calcium-sensing receptor (CaR), taste receptors type-1, and G protein-coupled receptor, family C, group 6, member A (GPRC6A) in GLUTag cells. As L-ornithine, potent stimuli for GPRC6A, significantly increased the intracellular calcium concentration ([Ca2+]i), we decided to analyze GPRC6A function in GLUTag cells. We examined whether L-ornithine provokes GLP-1 secretion from GLUTag cells by using live cell imaging and ELISA analyses. We found that L-ornithine induces GLP-1 secretion in a dose-dependent manner. To clarify by which signaling L-ornithine induces GLP-1 secretion, we examined the effects of GPRC6A antagonist, phospholipase C and inositol triphosphate inhibitors on L-ornithine-induced GLP-1 secretion. Those inhibitors significantly decreased the amount of L-ornithine-induced GLP-1 secretion. Furthermore, depletion of endogenous GPRC6A expression by small interference RNA inhibited L-ornithine-induced GLP-1 secretion. These results suggest that L-ornithine induces GLP-1 secretion from GLUTag cells through Gq-coupled receptor, GPRC6A, and L-ornithine might suppress appetite and regulate energy balance.	O1-9-4-2 POMCおよびAgRPニューロンでのSirt1過剰発現は、レプチン感受性改善・摂食抑制・エネルギー消費亢進をもたらし、エネルギーバランスを負に制御する Sirt1 overexpression in POMC and AgRP neurons leads to a negative energy balance via increased energy expenditure and decreased food intake through improved leptin sensitivity ○佐々木努1, 新福摩弓1, 菊池司1, ヴィナスサンティ1, 橋本博美1, 小林雅樹1, 北村忠弘1 ○Tsutomu Sasaki1, Mayumi Shimpuku1, Osamu Kikuchi1, Vina Y Susanti1, Hiromi Yokota-Hashimoto1, Masaki Kobayashi1, Tadahiro Kitamura1 群馬大学　生体調節研究所　代謝シグナル解析分野1 Institute for Molecular and Cellular Regulation, Gunma Univ, Maebashi, Japan1 Anorexigenic proopiomelanocortin (POMC)-positive neurons and orexigenic agouti-related peptide (AgRP)-positive neurons, located in the arcuate nucleus of the hypothalamus (ARC), play key roles in the hypothalamic control of the whole body energy balance. The NAD+-dependent deacetylase Sirt1 is implicated in improved health by caloric restriction through energy metabolism regulation, and its expression decreases with age in ARC. Meanwhile, energy expenditure gradually decreases with age in humans, and it is accompanied by increase in body weight.The results of murine Sirt1 loss-of-function studies in POMC and in AgRP neurons have been inconsistent, and the roles of hypothalamic Sirt1 in regulating the whole body energy balance remain controversial. Here we show that conditional overexpression of Sirt1 in POMC or AgRP neurons in mice leads to a negative energy balance. Sirt1 overexpression in POMC neurons improved leptin sensitivity, stimulated energy expenditure, lipolysis, and conversion of subcutaneous white adipocytes to beige cells via increased sympathetic activity to adipose tissues. Overexpression of Sirt1 in AgRP neurons also improved leptin sensitivity and suppressed food intake; these effects resulted in a lean phenotype. Notably, the suppression of age-dependent weight gain by Sirt1 overexpression in these neurons was countered by a high-fat, high-sucrose diet. Our results indicate that in the central melanocortin neurons, Sirt1 helps achieve a negative energy balance by modulating leptin sensitivity and regulating both food intake and energy expenditure. These functions can be suppressed by diet-induced obesity.
O1-9-4-3 ヒト末梢血における慢性心理的ストレス応答性マイクロRNAの同定 Chronic academic stress increases a group of microRNAs in peripheral blood ○桑野由紀1, 本田真奈美1, 梶田敬介1, 赤池瑶子1, 藤田絹代1, 佐竹譲1, 西田憲生1, 増田清士1, 六反一仁1 ○Yuki Kuwano1, Manami Honda1, Keisuke Kajita1, Youko Akaike1, Kinuyo Fujita1, Yuzuru Satake1, Kensei Nishida1, Kiyoshi Masuda1, Kazuhito Rokutan1 徳島大院・ヘルスバイオサイエンス研究部・ストレス制御医学1 Dept Stress Science, Inst Health Biosciences, Univ of Tokushima, Tokushima1 Introduction: Non-coding microRNAs (miRNAs) are suggested to serve fundamental roles in cellular stress responses and in coping with sudden environmental changes in experimental animals. However, physiological roles of psychological stress-responsive miRNAs are not fully understood. Methods: To examine whether long-lasting stressful situations cause miRNA responses in peripheral blood, miRNA expression profiles were measured using a human miRNA microarray in 25 healthy male medical students (22.4 ± 0.8 years old, mean ± SD) two months and two days before the national examination for medical practitioners. Blood obtained one month after the examination was used as a baseline control. Results: Levels of seven miRNAs (miR-16, -20b, -26b, -29a, -126, -144 and -144*) were significantly elevated during the pre-examination period in association with significant down-regulation of their target mRNAs (WNT4, CCM2, MAK, and FGFR1 mRNAs) two days before the examination. State anxiety assessed two months before the examination was positively and negatively correlated with miR-16 and its target WNT4 mRNA levels, respectively. Fold changes in miR-16 levels from two days before to one month after the examination were inversely correlated with those in WNT4 mRNA levels over the same time points. We also confirmed the interaction between miR-16 and WNT4 3'UTR in HEK293T cells overexpressing FLAG-tagged WNT4 3'UTR and miR-16. Conclusions: Taken together, our results suggest that a distinct group of circulating miRNAs may participate in the integrated response to chronic academic stress in healthy young men.	O1-9-4-4 Early postnatal development of electrical, synaptic and hormonal responses in the mouse basolateral nucleus of the amygdala ○Peter Koppensteiner1,2,3, Daisuke Yamada1,3, Shu Aizawa1,3, Tomohiro Kabuta1,3, Stefan Boehm2, Keiji Wada1,3, Masayuki Sekiguchi1,3 Dept Degenerat Neurol Dis, Natl Inst Neurosci, Natl Centr Neurol Psychiat, Tokyo, Japan1, Dept of Neurophys Pharmacol, Centr Physiol Pharmacol, Med Univ Wien, Vienna, Austria2 In humans, experiences of trauma during childhood are thought to be risk factors for developing amygdala-associated mental disorders in later life. Correspondingly, in rodents, exposure to early-life stress has been shown to affect neuronal circuitry and emotional behavior in adulthood, indicating a significant impact of stress upon brain development. However, the immediate neonatal development of pyramidal neurons of the amygdala, a structure central in the processing of emotions, and the effect of the stress-hormone corticosterone upon it have not been characterized from an electrophysiological point of view. Therefore, we investigated electrophysiological properties of neurons of the basolateral nucleus of the amygdala (BLA), a major quasinucleus of the amygdala, and the effects of corticosterone in neonatal and adolescent mice upon these properties. In addition, we assessed the effect of neonatal corticosterone exposure using behavioral and molecular biological methods. We found immature BLA neurons to be characterized by high excitability, low spontaneous synaptic activity and low-amplitude action potentials. Furthermore, neonatal BLA neurons were capable of responding to 100 nM corticosterone with increased mEPSC frequencies within 20 minutes. Neonatal corticosterone exposure increased BLA excitability, enhanced disinhibited synchronized firing and reduced fear extinction learning in adolescence. Overall, our study revealed that neonatal BLA pyramidal neurons are highly excitable and display long- and short-term responsiveness to glucocorticoid exposure in the neonatal period.

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