The rhythmic activity of neurons in arcuate nucleus and paraventricular nucleus regulate feeding behavior and metabolism.

• Project/Area Number: 15K09442
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Endocrinology
• Research Institution: Wakayama Medical University (2018); Jichi Medical University (2015-2017)
• Principal Investigator: Nakata Masanori 和歌山県立医科大学, 医学部, 教授 (10305120)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 摂食行動 / 室傍核 / Nesfatin-1 / FGF21 / メタボリックシンドローム / 弓状核 / 概日リズム / 摂食調節 / エネルギー代謝 / 生活習慣病 / 時計遺伝子 / NUCB2/Nesfatin-1 / BMAL1 / AgRP / Oxytocin / NUCB2

Outline of Final Research Achievements

Nesfatin-1, an anorectic peptide processed from nucleobindin-2 (NUCB2), is expressed in the hypothalamus including the paraventricular nucleus (PVN). PVN specific NUCB2 knockdown induces LP-selective hyperphagia and reduction of PVN Oxt mRNA expression as early as 3-4 weeks after AAV treatment, which were followed by increases in daily food intake and body weight in later period. These results reveal that the endogenous nesfatin-1 neuron in PVN regulates PVN oxytocin and consequently the energy balance. Furthermore, we clarified that fibroblast growth factor (FGF) 21 is a novel regulator of nesfatin-1 neurons. ICV injection of FGF21 markedly suppressed food intake in fed mice with elevated blood glucose. FGF21 failed to suppress food intake in PVN-preferential Nucb2 knockout mice. These results demonstrate that the PVN nesfatin-1 neurons physiologically sense key peripheral metabolic signals, and thereby regulate circadian feeding rhythm and glucose metabolism.

Academic Significance and Societal Importance of the Research Achievements

生活リズムの乱れ、特に食行動リズムの乱れは生活習慣病を増悪させる。食行動リズムの形成機構を解明することは、生活習慣病の病態の解明および予防・治療に有用である。本研究では、食行動リズムは、室傍核Nesfatin1ニューロンの活動リズムが制御する事を示した。さらにNesfatin-1ニューロンの上流はFGF21、下流はOxytocinニューロンである事も示した。この結果から、FGF21、Nesfatin-1、Oxytocinを標的とした生活習慣病の予防・治療法確立への展開が期待できる。さらに、弓状核-室傍核軸を切り口として血圧制御機構の分子基盤を与え、治療介入点を示すことが出来た。

Research Products

• [Journal Article] Central insulin action induces activation of paraventricular oxytocin neurons to release oxytocin into circulation. (2018)
  • Author(s): Zhang B, Nakata M, Nakae J, Ogawa W, Yada T.
  • Journal Title: Sci Rep. Volume: 8 Issue: 1 Pages: 10415-10415
  • DOI: 10.1038/s41598-018-28816-w
  • NAID: 120006491584
  • Peer Reviewed / Open Access
• [Journal Article] Protective role of AgRP neuron's PDK1 against salt-induced hypertension. (2018)
  • Author(s): Zhang B, Nakata M, Lu M, Nakae J, Okada T, Ogawa W, Yada T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 500 Issue: 4 Pages: 910-916
  • DOI: 10.1016/j.bbrc.2018.04.192
  • Peer Reviewed
• [Journal Article] GLP-1 receptor agonist liraglutide exerts central action to induce β-cell proliferation through medulla to vagal pathway in mice. (2018)
  • Author(s): Kumari P, Nakata M, Zhang BY, Otgon-Uul Z, Yada T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 499 Issue: 3 Pages: 618-625
  • DOI: 10.1016/j.bbrc.2018.03.199
  • Peer Reviewed
• [Journal Article] Weaning stage hyperglycemia induces glucose-insensitivity in arcuate POMC neurons and hyperphagia in type 2 diabetic GK rats (2018)
  • Author(s): Ando Akihiko、Gantulga Darambazar、Nakata Masanori、Maekawa Fumihiko、Dezaki Katsuya、Ishibashi Shun、Yada Toshihiko
  • Journal Title: Neuropeptides Volume: 68 Pages: 49-56
  • DOI: 10.1016/j.npep.2018.02.001
  • Peer Reviewed / Open Access
• [Journal Article] The effects of adjunctive intranasal oxytocin in patients with schizophrenia. (2018)
  • Author(s): Ota M, Yoshida S, Nakata M, Yada T, Kunugi H.
  • Journal Title: Postgrad Med. Volume: 130 Issue: 1 Pages: 122-128
  • DOI: 10.1080/00325481.2018.1398592
  • Peer Reviewed
• [Journal Article] GLP-1 release and vagal afferent activation mediate the beneficial metabolic and chronotherapeutic effects of D-allulose (2018)
  • Author(s): Iwasaki Yusaku、Sendo Mio、Dezaki Katsuya、Hira Tohru、Sato Takehiro、Nakata Masanori、Goswami Chayon、Aoki Ryohei、Arai Takeshi、Kumari Parmila、Hayakawa Masaki、Masuda Chiaki、Okada Takashi、Hara Hiroshi、Drucker Daniel J.、Yamada Yuichiro、Tokuda Masaaki、Yada Toshihiko
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 113-113
  • DOI: 10.1038/s41467-017-02488-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Activation of AMPK-Regulated CRH Neurons in the PVH is Sufficient and Necessary to Induce Dietary Preference for Carbohydrate over Fat. (2018)
  • Author(s): Okamoto S, Sato T, Tateyama M, Kageyama H, Maejima Y, Nakata M, Hirako S, Matsuo T, Kyaw S, Shiuchi T, Toda C, Sedbazar U, Saito K, Asgar NF, Zhang B, Yokota S, Kobayashi K, Foufelle F, Ferré P, Nakazato M, Masuzaki H, Shioda S, Yada T, Kahn BB, Minokoshi Y.
  • Journal Title: Cell Rep. Volume: 22 Issue: 3 Pages: 706-721
  • DOI: 10.1016/j.celrep.2017.11.102
  • NAID: 120007001417
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fibroblast growth factor 21, assisted by elevated glucose, activates paraventricular nucleus NUCB2/Nesfatin-1 neurons to produce satiety under fed states. (2017)
  • Author(s): Santoso P, Nakata M, Shiizaki K, Boyang Z, Parmila K, Otgon-Uul Z, Hashimoto K, Satoh T, Mori M, Kuro-O M, Yada T
  • Journal Title: Sci Rep Volume: 印刷中 Issue: 1 Pages: 45819-45819
  • DOI: 10.1038/srep45819
  • Peer Reviewed / Open Access
• [Journal Article] PDK1-FoxO1 pathway in AgRP neurons of arcuate nucleus promotes bone formation via GHRH-GH-IGF1 axis. (2017)
  • Author(s): Sasanuma H, Nakata M, Parmila K, Nakae J, Yada T.
  • Journal Title: Mol Metab. Volume: 6 Pages: 428-439
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of Y1 receptor signaling improves islet transplant outcome (2017)
  • Author(s): Loh Kim、Shi Yan-Chuan、Walters Stacey、Bensellam Mohammed、Lee Kailun、Dezaki Katsuya、Nakata Masanori、Ip Chi Kin、Chan Jeng Yie、Gurzov Esteban N.、Thomas Helen E.、Waibel Michaela、Cantley James、Kay Thomas W.、Yada Toshihiko、Laybutt D. Ross、Grey Shane T.、Herzog Herbert
  • Journal Title: Nature Communications Volume: 8 Issue: 1 Pages: 490-490
  • DOI: 10.1038/s41467-017-00624-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Suprachiasmatic Vasopressin to Paraventricular Oxytocin Neurocircuit in the Hypothalamus Relays Light Reception to Inhibition of Feeding Behavior. (2017)
  • Author(s): Santoso P, Nakata M, Ueta Y, Toshihiko Yada T
  • Journal Title: Am J Physiol Endocrinol Metab. Volume: 印刷中 Issue: 4 Pages: E478-E488
  • DOI: 10.1152/ajpendo.00338.2016
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] PDK1-FoxO1 pathway in AgRP neurons of arcuate nucleus promotes bone formation via GHRH-GH-IGF1 axis. (2017)
  • Author(s): Sasanuma H, Nakata M, Kumari P, Nakae J, Yada T
  • Journal Title: Molecular Metabolism Volume: 6(5) Issue: 5 Pages: 428-439
  • DOI: 10.1016/j.molmet.2017.02.003
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] AAV-mediated IL-10 gene transfer counteracts inflammation in the hypothalamic arcuate nucleus and obesity induced by high-fat diet. (2017)
  • Author(s): Nakata M, Yamamoto S, Okada T, Yada T.
  • Journal Title: Neuropeptides. Volume: 62 Pages: 87-92
  • DOI: 10.1016/j.npep.2016.11.009
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] High-fat diet augments VPAC1 receptor-mediated PACAP action on the liver, inducing LAR expression and insulin resistance. (2016)
  • Author(s): Nakata M, Zhang B, Yang Y, Okada T, Shintani N, Hashimoto H, Yada T.
  • Journal Title: J Diabetes Res Volume: 2016 Pages: 9321395-9321395
  • DOI: 10.1155/2016/9321395
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Paraventricular NUCB2/nesfatin-1 supports oxytocin and vasopressin neurons to control feeding behavior and fluid balance in male mice. (2016)
  • Author(s): Nakata M, Gantulga D, Santoso P, Zhang B, Masuda C, Mori M, Okada T, Yada T.
  • Journal Title: Endocrinology Volume: 未定
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Betatrophin expression is promoted in obese hyperinsulinemic type 2 but not type 1 diabetic mice. (2016)
  • Author(s): Li E, Nakata M, Shinozaki A, Yang Y, Zhang B, Yada T.
  • Journal Title: Endocrine Ｊ Volume: 未定
  • NAID: 130005253784
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] IL-10 gene transfer upregulates arcuate POMC and ameliorates hyperphagia, obesity and diabetes by substituting for leptin. (2016)
  • Author(s): Nakata M, Yamamoto S, Okada T, Gantulga D, Okano H, Ozawa K, Yada T.
  • Journal Title: Int J Obes (Lond). Volume: 40 Issue: 3 Pages: 425-433
  • DOI: 10.1038/ijo.2015.201
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Fasted/fed states regulate postsynaptic hub protein DYNLL2 and glutamatergic transmission in oxytocin neurons in the hypothalamic paraventricular nucleus. (2016)
  • Author(s): Suyama S, Kodaira-Hirano M, Otgon-Uul Z, Ueta Y, Nakata M, Yada T.
  • Journal Title: Neuropeptides. Volume: 56 Pages: 115-123
  • DOI: 10.1016/j.npep.2015.08.008
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A novel insulinotropic mechanism of whole grain-derived γ-oryzanol via the suppression of local dopamine D2 receptor signalling in mouse islet. (2015)
  • Author(s): Kozuka C, Sunagawa S, Ueda R, Higa M, Ohshiro Y, Tanaka H, Shimizu-Okabe C, Takayama C, Matsushita M, Tsutsui M, Ishiuchi S, Nakata M, Yada T, Miyazaki JI, Oyadomari S, Shimabukuro M, Masuzaki H.
  • Journal Title: Br J Pharmacol Volume: 172 Issue: 18 Pages: 4519-4534
  • DOI: 10.1111/bph.13236
  • Peer Reviewed
• [Journal Article] Arcuate Na+,K+-ATPase senses systemic energy states and regulates feeding behavior through glucose-inhibited neurons. (2015)
  • Author(s): Kurita H, Xu KY, Maejima Y, Nakata M, Dezaki K, Santoso P, Yang Y, Arai T, Gantulga D, Muroya S, Lefor AK, Kakei M, Watanabe E, Yada T.
  • Journal Title: Am J Physiol Endocrinol Metab. Volume: 309
  • Peer Reviewed
• [Journal Article] Paraventricular NUCB2/nesfatin-1 is directly targeted by leptin and mediates its anorexigenic effect (2015)
  • Author(s): Darambazar G, Nakata M, Okada T, Wang L, Li E, Shinozaki A, Motoshima M, Mori M, Yada T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 456（4） Issue: 4 Pages: 913-918
  • DOI: 10.1016/j.bbrc.2014.12.065
  • Peer Reviewed / Open Access
• [Presentation] GLP-1受容体作動薬Liraglutideの中枢作用による膵β細胞増殖促進 (2018)
  • Author(s): 中田正範
  • Organizer: 第６１回日本糖尿病学会
• [Presentation] 弓状核AgRPニューロンの室傍核Nesfatin-1ニューロンを介した血圧調節回路 (2018)
  • Author(s): 中田正範
  • Organizer: 第３９回日本肥満学会
• [Presentation] GLP-1受容体作動薬Liraglutideの中枢性血糖降下作用のメカニズム． (2017)
  • Author(s): 中田正範，Kumari Parmila，矢田俊彦
  • Organizer: 第90回日本内分泌学会学術総会
• [Presentation] GLP-1受容体作動薬Liraglutideの中枢性血糖降下作用のメカニズム (2017)
  • Author(s): 中田正範，Parmila Kumari，矢田俊彦
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] 弓状核AgRPニューロンのPDK1シグナルを起点とした血圧調節経路． (2017)
  • Author(s): 中田正範，中江淳，Parmila Kumari，張博洋，小川渉，矢田俊彦
  • Organizer: 第38回日本肥満学会
• [Presentation] FGF21の中枢作用における室傍核Nesfatin-1/NUCB2ニューロンの役割 (2016)
  • Author(s): 中田正範，Putra Santoso，張博洋，矢田俊彦
  • Organizer: 第37回日本肥満学会
  • Place of Presentation: 東京ビックサイト 東京
  • Year and Date: 2016-10-07
• [Presentation] 視床下部室傍核Nesfatin-1ニューロンによる摂食・エネルギー代謝調節 (2016)
  • Author(s): 中田正範
  • Organizer: 第21回アディポサイエンスシンポジウム
  • Place of Presentation: 千里ライフセンター 京都
  • Year and Date: 2016-08-20
  • Invited
• [Presentation] FGF21の中枢性摂食抑制作用と仲介ニューロンの同定 (2016)
  • Author(s): 中田正範，Putra Santoso，張博洋，楊怡飛，矢田俊彦
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: 国際会議場 京都
  • Year and Date: 2016-05-19
• [Presentation] 視床下部弓状核Na+,K+-ATPaseはグルコセンサーとして摂食行動を制御する (2016)
  • Author(s): 矢田俊彦，栗田英治，中田正範
  • Organizer: 第93回日本生理学会大会
  • Place of Presentation: 札幌
  • Year and Date: 2016-03-22
• [Presentation] Paraventricular nucleus NUCB2/nesfatin-1 neurons regulate feeing and glucose metabolism. (2015)
  • Author(s): Nakata M, Santoso P, Wang L, Yada T
  • Organizer: Keystone Symposia Conference,
  • Place of Presentation: Ｋｙｏｔｏ
  • Year and Date: 2015-10-25
  • Int'l Joint Research
• [Presentation] 室傍核Nesfatin-1 ニューロンによるバゾプレッシン発現と血圧の調節 (2015)
  • Author(s): 中田正範，王磊，楊怡飛，矢田俊彦
  • Organizer: 第36回日本肥満学会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-02
• [Presentation] インクレチンPACAPによる肝臓インスリン感受性と糖新生の調節 (2015)
  • Author(s): 中田正範，矢田俊彦
  • Organizer: 第58回日本糖尿病学会年次学術集会、第2回肝臓と糖尿病・代謝研究会
  • Place of Presentation: 下関
  • Year and Date: 2015-05-23
• [Presentation] 室傍核NUCB2/Nesfatin-1ノックダウンマウスの解析：摂食概日リズム障害と内臓肥満 (2015)
  • Author(s): 王磊，中田正範，矢田俊彦
  • Organizer: 第88回日本内分泌学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2015-04-23
• [Remarks] 和歌山県立医科大学生理学第二
  • URL: http://www.wakayama-med.ac.jp/dept/igakubu/160414/index.html
• [Remarks] 自治医科大学生理学講座統合生理学部門
  • URL: http://www.jichi.ac.jp/physio2/physiol_new_HP2008/index.htm
• [Remarks] 自治医科大学生理学講座 統合生理学部門
  • URL: http://www.jichi.ac.jp/physio2/physiol_new_HP2008/index.htm